Organogels as novel carriers for dermal and topical drug delivery vehicles

Article abstract of DOI:10.1016/j.tet.2016.10.009

Aminoalcohol based bis-(aminoalcohol)oxalamides (BAOAs) (1,6-amino alcohol=leucinol, isoleucinol, valinol, phenylglycinol, phenylalaninol and 2-amino-1-butanol) have been explored to develop drug depot systems and illustrated as a novel dermal and topical drug delivery vehicle for non-steroidal anti-inflammatory drug molecules. FAE's (Fatty acid ethyl and isopropyl esters) with different chain lengths, ethyl laurate, ethyl myristate, ethyl palmitate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, have been chosen as they are biocompatible organic fluids used typically in cosmetic industry. Ibuprofen (Ib), acting as a model drug, was entrapped in the supramolecular organogels. The release behavior of Ib molecules in the supramolecular organogels was investigated by using UV–vis spectroscopy. The influence of the organogelator and drug concentration, pH values of the accepting media, and nature of solvent (different FAE's) on the release behavior of Ib was investigated under static conditions. The results indicated that the release rate of Ib from the supramolecular organogels was effectively retarded with an increase of the organogelator concentration. Also, the release rates of Ib increased on increasing the Ib content. Furthermore, the release behavior of Ib was found to be different at various pH values in buffers as accepting media. The study of the release kinetics indicated that the release behavior of Ib was in accord with the Higuchi equation and the diffusion-controlled mechanism involved in the Fickian model. These observations indicate that bis-(aminoalcohol)oxalamides gels may act as delivery vehicles for non-steroidal anti-inflammatory drug molecules and also show that the release profiles for such systems can be fine-tuned by the correct choice of gelator-FAE combination.

Full text of DOI:10.1016/j.tet.2016.10.009

Accepted Manuscript
Organogels as novel carriers for dermal and topical drug delivery vehicles
Serhat Uzan, Deniz Barış, Mehmet Çolak, Haluk Aydın, Halil Hoşgören
PII:
S0040-4020(16)31014-6
10.1016/j.tet.2016.10.009
TET 28150
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 April 2016
Revised Date: 19 September 2016
Accepted Date: 4 October 2016
Please cite this article as: Uzan S, Barış D, Çolak M, Aydın H, Hoşgören H, Organogels as
novel carriers for dermal and topical drug delivery vehicles, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.10.009.
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ACCEPTED MANUSCRIPT
Graphical abstract
First 8 h period of released drug amount depending on drug loading quantity of Bis(PhAlaOH)/ LEE gel.

Organogels As Novel Carriers For Dermal And Topical Drug Delivery
ACCEPTED MANUSCRIPT
Vehicles
a
b
a
a
a
Serhat Uzan , Deniz Barış , Mehmet Çolak , Haluk Aydın , Halil Hoşgören*,
a
Department of Chemistry, University of Dicle, 21280 Diyarbakır, Turkey
Department of Chemistry, University of Batman, Batman, Turkey
b
ABSTRACT
Aminoalcohol based bis-(aminoalcohol)oxalamides (BAOAs) (1,6-amino alcohol=leucinol, isoleucinol, valinol,
phenylglycinol, phenylalaninol and 2-amino-1-butanol) have been explored to develop drug depot systems and
illustrated as a novel dermal and topical drug delivery vehicle for non-steroidal anti-imflammotory drug
molecules. FAE’s (Fatty acid ethyl and isopropyl esters) with different chain lengths, ethyl laurate, ethyl
myristate, ethyl palmitate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, have been chosen as
they are biocompatible organic fluids used typically in cosmetic industry. Ibuprofen (Ib), acting as a model drug,
was entrapped in the supramolecular organogels. The release behavior of Ib molecules in the supramolecular
organogels was investigated by using UV–Vis spectroscopy. The influence of the organogelator and drug
concentration, pH values of the accepting media, and nature of solvent (different FAE’s) on the release
behavior of Ib was investigated under static conditions. The results indicated that the release rate of Ib from
the supramolecular organogels was effectively retarded with an increase of the organogelator concentration.
Also, the release rates of Ib increased on increasing the Ib content. Furthermore, the release behavior of Ib was
found to be different at various pH values in buffers as accepting media. The study of the release kinetics
indicated that the release behavior of Ib was in accord with the Higuchi equation and the diffusion-controlled
mechanism involved in the Fickian model. These observations indicate that bis-(aminoalcohol)oxalamides gels
may act as delivery vehicles for non-steroidal anti-imflammotory drug molecules and also show that the release
profiles for such systems can be fine-tuned by the correct choice of gelator-FAE combination.
Keywords: Gels; LMWOGs (Low Molecular Weight Organojelators), Controlled release; Drug delivery systems
Formulation Formulation vehicle FTIR
;
;
;
*
Corresponding authorTel.:+90(412)2488550; fax: +90(412)2488300.
E-mail address: hosgoren@dicle.edu.tr(H.Hoşgören)
1

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1
. Introduction
Recently, more and more examples of LMWGs for water (i.e. hydrogelators) have
1
,2
appeared in the literature in a move towards useful, new materials for drug delivery
vehicle. However, LMWGs for organic fluids have until now mainly been used to gelate
3-6
organic solvents and to study the relationship between the structure of the molecules and
their gelating capabilities. Organogels have currently occupield a signifigant place in research
and industry, especially those called low molecular weight gelators (LMWGs) have a special
7
-11
place application in drug release in phameceuticals.
The fisrt study of this kind use
reported by van Esch and coworkers. N-N’-dibenzoyl-L-Cystine (DBC) was used as the LMWG
1
2
gelator.
Organogels present very interesting advantages as drug delivery formulations, amongst which
their ease of preparation and administration. Optimization of sustained drug release is
generally thought to be possible by fine tuning the LMWG structure and possibly the nature
13
of the organic phase. Control of drug dosing in terms of quantity, location and time is a key
goal for drug delivery science because improved control maximizes the therapeutic effect
1
4,15
while minimizing side effects.
Also organogels are moisture insensitive. They enhance
skin penetration. Because their organic character also resists microbial contamination; their
gelation and entrapment procedure is very simple and easy to handle. Their biocompatibile,
biodegradable and non-immunogenic properties make them safe for long term application.
This gel-forming nature has been used to develop drug depot systems. Nevertheless,
organogels have some advantages as a drug carrier system. Organogelators remain largely
8
unexplored in the field of drug delivery.
On the other hand, there is currently a high level of interest in using the skin as a route for
drug delivery; due to its accessibility, skin has been considered as a potential route for
systemic drug administration and research into transdermal drug delivery has expanded
greatly over the last two decades. Now-a-days exposure to UV rays is giving way to skin cancer
in people. Organogels can become a viable alternative, if anticancer agents are delivered
9
through them which have not been tried till date.
Passage of drug molecules through the skin could be an important and rather
troublesome stage in percutaneous drug delivery. Among the various methods for improving
the passage of drug molecules through the skin is the use of penetration enhancers. The use
of fatty acid esters and related alcohols as enhencers for drug permeation is of great interest
2

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for both topical and transdermal drug delivery. This mode of administration may help avoid
typical side effects associated with oral administration of nonsteroidal anti-imflammotory
drug (NSAIDs) such as gastric irritation, diarrhea, nausea, abdominal pain and flatulence.
Furthermore, it can be used as a supplement to oral therapy for better treatment of
conditions such as arthritis.
On the other hand, one of the most difficult things for the development of low molecular
weight gelators is how to stabilize the formed gel, in the other words, how to prevent the
16
transformation of a metastable gel into a crystalline state. Also raw materials like lecithin
and other natural source materials are also expensive and unavailable on large scale
production. Thus, to overcome these obstacles, amino acid based synthetic organogelators
1
7,18
were used instead of these natural raw materials.
To this end, a new gel formulation for topical and transdermal applications of NSAIDs with
increased enhancer properties has been prepared. Organic fluids having enhancer properties
have been chosen as gelation solvents for a new drug relasing system. For this purpose FAE’s
(Fatty acid ethyl and isopropyl esters) with different chain lengths, ethyl laurate, ethyl
myristate, ethyl palmitate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, have
been chosen as biocompatible organic fluids which are widely used in cosmetic industry.
NSAID as an active pharmaceutical ingredient; the gelators chosen for these purposes are
chiral bis(aminoalcohol)oxalamides (BAOAs) 1-6: aminoalcohol: leucinol (SS-1), izoleucinol
(SS-2), valinol (SS-3), phenylalaninol (SS-4), phenylglycinol (SS-5), and R-2-aminobutanol (RR-
6
) respectively, some of them well-known LMWGs for organic fluids the properties of which
1
9,20
have been reported in several papers.
bis(aminoalcohol)oxalmide gelators
O
R
O
H
H
N
N
R
N
H
N
H
OH
O
OH
O
OH
OH
(R,R)-6
(S,S)-1
R = iso-butyl
R = sec-butyl
R = iso-propyl
R = benzyl
(S;S)-2
(S,S)-3
(S,S)-4
(S,S)-5
R = phenyl
3

Although the gelation capability of these chiral bis(amino alcohol) oxalamide gelators for
ACCEPTED MANUSCRIPT
various organic solvents and their mixtures have already been reported, their gel properties
1
9,20
in FAE’s which are used in the pharmaceutical industry have not yet been characterized.
In this study, the gelation properties of BAOA gelators, dissolved in phamaceutically
acceptable organic solvents, have been evaluated. Finally, the potential of these organogels
for the sustained delivery of NSAID’s such as ibuprofen has been addressed. In this paper,
ibuprofen is chosen as a model drug since this NSAID can interact with the gelator via not
only van der Waals interactions but also hydrogen bonding due to possessing a carboxylic
acid moiety and can therefore be retained in the gel. Moreover, ibuprofen is adequately
soluble in water and UV-active, making its release from gels easy to follow by UV-Vis
spectroscopy.
2
. Materials and method
All chemicals were reagent grade unless otherwise specified. They were purchased from
Sigma-Aldrich or Fluka Chemical Company. Silica gel 60 (Merck, 0.040-0.063 mm) were used
for flash column chromatography; the synthetic procedures were followed by Thin-layer
chromatography (TLC) performed on silica-gel-coated Merck 60 F254 silica plates, and
visualized using a UV lamp (254nm) or I vapors. All reactions were carried out under
2
nitrogen or argon atmosphere with dry solvent under anhydrous conditions, unless
otherwise noted. All chemicals were of the best commercially available grade and were used
without purification. All chemicals for the synthesis of compounds were purchased from
commercial suppliers. Solvents were purified according to literature methods and stored
over molecular sieves. The purity of the products was proved by elemental analysis and TLC,
1
13
also by IR, H NMR and C NMR spectroscopy (see experimental section).
2
.1. Apparatus for measurements
Melting points were determined by a Gallenkamp Model apparatus with open capillaries
and are uncorrected. Elemental analyses C, H and N were performed using a Carlo-Erba
108 Model apparatus; and the results are within ± 0.3% of the theoretical values. Specific
1
Rotations were taken on a Perkin-Elmer 341 Model Polarimeter. Infrared spectra were
recorded on a MATTSON Model 1000 Spectrophotometer. Temperature dependent IR
1
spectra were taken with a Specac GS20730 model heating jacket. H NMR (400 MHz) and
1
3
C NMR (100 MHz) spectra were recorded on a Bruker AV400 High Performance Digital FT-
4

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NMR Spectrometer. The chemical shifts (δ) and coupling constants (J) were expressed in
parts per million and Hertz, respectively. pH measurements were carried out with a
METTLER TOLEDO GmbH 8603 pH meter. UV–Vis spectroscopy was carried out on a
VARIAN UV1010M211 spectrophotometer. The SEM observations were carried out using a
FEI Quanta 250 FEG field emission scanning microscope.
2
.2. General procedure for preparation of bis(amino alcohol oxalyl amides) [1-6]:
Bis(amino alcohol oxalyl amides) [1-6] were synthesized by modified literature
1
9,22
23
methods.
A solution of aminoalcohol (0.032mol) in methanol (25 mL) was slowly
added dropwise over a 30 min period to a solution of dimethyl oxalate (1.9 g, 0.016 mol) at
room temperature. While the reaction mixture was stirred, a white solid immediately
formed which was then collected and washed with a small portion of diethyl ether to give
the pure compound.(See SI)
2
.3. GelationTest
A typical gelation experiment was carried out as follows: a weighed amount of gelator, or
gelator and Ib were mixed with fatty acid ethyl and isopropyl esters of 1 mL (FAE’s: Lauric,
myristic and palmitic acid ethyl and isopropyl esters) in a septum-capped 4 mL glass vial
(internal diameter: 10 mm) and heated until the solid dissolved, after which the solution was
o
allowed to cool and holded in a constant temperature bath at 25 C. Gelation was
considered to have occurred when a homogeneous substance was obtained, which exhibited
24
no gravitational flow upon inversion of the vial.
2
.4. Determination of Gel- sol transition temperatures (Tg)
All gel-to-sol transition temperatures (T ) were determined using the ‘‘dropping ball’’
g
method, which consists of carefully placing a stainless steel ball (250 mg, 4 mm in diameter)
on top of already prepared gels (Section 2.3) in 2 mL glass vials and subsequently placing
2
5
these vials in a heating block. The temperature of the heating block with increased by
o
1
C/min. and the T defined as the temperature at which the steel ball reaches the bottom
g
o
of the vial. Errors in all T values are ±3 C.
g
2
.5. Scanning electron microscope
The sample were prepared as follow: The dried sample for electron microscopic analysis
(TEM/SEM) is often prepared by the deposition of a gel sample followed by drying in
vacuum. However, for organogels formed by organic fluids with a high boiling point, such as
FAE’s, the deposition method is unusable because it cannot produce a dried sample
5

ACCEPTED MANUSCRIPT
(
xerogel). In the currently used systems, sample preparation is carried out by a re-
2
6
precipitation method. Because bis(aminoalcohol)oxalamides compounds are insoluble in
hexane at room temperature, a quick precipitation from FAE gel in hexane is very useful for
sample preparation. There is some riskand morphological change during this precipitation
process. Although the organogel is destroyed by shaking in hexane, the nanoscaled network
is maintained by the quick precipitation
2
.6. FT-IR Study
FT-IR spectroscopy was performed by using a spectroscopy cell with a CaF window and
2
-
1
5
0 µm spacers operated with a 2 cm resolution in 32 scans. The temperature-controlled
FTIR spectra were measured by using an automatic temperature-control cell unit (Specac
GS20730 model heating jacket) with a vacuum-tight liquid cell (specac Inc., P/N 20502, path
length 50 µm) fitted with CaF windows.
2
2
.7. The drug loading experiment of Bis(PhAlaOH) in FAEs
A typical drug loading experiment was carried out as follows: a weighed amount of gelator
3
.5 mg Bis(PhAlaOH), and 1 mg Ib were mixed with fatty acid ethyl and isopropyl esters in 1
mL (FAE’s: Lauric, myristic and palmitic acid ethyl and isopropyl esters) in a septum-capped 4
ml glass vial (internal diameter: 10 mm) and heated until the solid was dissolved, after which
o
the solution was allowed to cool and holded in a constant temperature bath at 25 C.
Gelation was considered to have occurred when a homogeneous substance was obtained,
which exhibited no gravitational flow upon inversion of the vial.
This drug loading experiment was repeated with the same gelator quantities but
increasing amount of Ib; until loading could be achieved without gel disruption. Here,
entrapment of Ib within the BAOA gel; until the solid drug does not dissolve or not give a
stable gel; as a consequence of the sol-to-gel process necessary to obtain a gel is defined the
maximum drug loading capacity of given gelator in the FAE fluids.
2
.8. Release studies
BAOA gels containing ibuprofen (Ib), prepared as described in Section 2.3, were allowed
o
to stand for 12 h at in a constant temperature bath at 25 C; after which 6 ml of phosphate
buffer at different pHs as a accepting medium was carefully placed on top of each gel (this
gel–solution two-phase system is stable for months). The release behavior of Ib was
6

ACCEPTED MANUSCRIPT
investigated depending on the gelator and drug concentration, structure of FAE’s, pH values
of the accepting medium. The release experiments were conducted under static conditions.
The calibration curves were obtained by gradual dilution of Ib aqueous solutions (160
mg/L) and measuring maximum absorbance at 222 nm using a UV–Vis spectrometer. The
curves showed that there was an excellent linear relationship between maximum
absorbance and concentration in the range of 0–20 mg/L. At the designed intervals of time,
3
mL of supernatant solution was taken out and filtered using filter paper. Subsequently, 3
mL of fresh buffer solution was added into the contents of the test-tube. The absorbance at
22 nm for each sample was measured and the concentration of the Ib which had been
2
released from the organogel was obtained based on the calibration curves. Release results at
any time were given as % release (the percentage of cumulative released ibuprofen at any
time which measurement was performed) or 100-% release (the percentage of Ib remaining
in the gel). All experiments were carried out in triplicate.
3
. Results and discussion
3
.1. Gel characterization
The result of gelation experiment with 1-6 in different FAE’s solvents are given in table 1.
Gelation efficiency is expressed by the minimum gel concentration (MGC g/L). Comparison
of the gelation properties of Bis(PhAlaOH Benzyl) (S,S)-4 reveals striking differences. The S,S-
4
derivative is able to gel all FAE’s solvents and efficiently gelled in these solvents at minimal
gelation concentrations. Whereas Bis(PhGlyOH Phenyl) S,S-5 is unable to gel any of tested
solvents. See Table 1 and Fig.1.
Table 1
0
a
Organogelation properties of bis (amino alcohol)oxalamide gelators at 25 C .
Bis(leuOH)
isobutyl((S,S)-1
Bis(IleuOH) sec-
butyl(S,S)-2
Bis(ValOH)
İsopropyl(S,S)-3
Bis(PhAlaOH
Benzyl(S,S)-4
Bis(PhGlyOH
Phenyl(S,S)-5
Bis(EthButOH
ethyl (R,R)-6
gelator
solvent
LEE
9 (OG)
1 (OG)
4 (OG)
1 (OG)
5 (TG)
5 (OG)
4 (OG)
5 (OG)
4 (OG)
4 (OG)
5 (OG)
4 (OG)
5 (OG)
7 (OG)
3 (OG)
4 (OG)
1 (OG)
1 (OG)
2 (TG)
1 (TG)
1 (TG)
1 (TG)
2 (TG)
3 (TG)
Ins
Ins
Ins
Ins
Ins
Ins
4 (OG)
3 (OG)
3 (OG)
3 (OG)
3 (OG)
3 (OG)
LIE
PEE
PIE
MEE
MIE
a
Values denote minimum gel concentration (MGC g/L), Ins=insoluble, OG: Opaque Gel,TG: Transparent Gel, LEE: Lauric acid Ethyl Ester,
MEE: Miristic acid Ethyl Ester, PEE:Palmitic acid Ethy lEster, LIE: Lauric acid Isopropyl Ester, MIE: Miristic acid Isopropyl Ester, PIE: Palmitic
acid Isopropyl Ester.
7

ACCEPTED MANUSCRIPT
Bis(PhAlaOH) /LIE
Bis(PhAlaOH) /PEE
Bis(EthButOH) /PEE
Bis(IleuOH)/LIE
Bis(ValOH) /PIE
Bis(leuOH) /LEE
Bis(leuOH) /MEE
Bis(PhAlaOH) /MIE
Fig.1.Selected photograph of bis(aminoalcohol) oxalamide gels in different FAEs.
Gel-to-sol transition temperatures (T ) for Bis(PhAlaOH) gels of different concentrations of
g
various FAE’s were determined by dropping ball measurements and show that the thermal
stability of the gels increases upon increasing the gelator concentration. See Fig. 2.
Fig.2. Plot of Tgel versus bis(aminoalcohol) oxalamidegelators concentration in lauric acid ethyl ester.
Further, detailed thermal behavior was analyzed by thermodynamic parameters for gel-
2
7,28
sol transition using van’t Hoff relationships.
If the sol-gel transition is comparable to
melting of crystals, the sol-gel transition enthalpy can be estimated by the van’t Hoff
relationship Eq. (1).
d lnCg
Hg
=
(1)
d 1/Tg
R
8

∆
H of 1-4, and 6 in FAEs (LEE, LIE, MEE, MIE, PEE, PIE) are reported in Table 2. And van’t Hoff
g
ACCEPTED MANUSCRIPT
plot of Bis(PhAlaOH) in different FAE’s (Faty acid ethyl esters) see Figs. 3, 4.
Fig.3. van’t Hoff plot of Bis(PhAlaOH) in different FAE’s (Faty acid ethyl esters).
Fig. 4. van’t Hoff plot of Bis(PhAlaOH) in different FAE’s (Faty acid isopropyl esters).
Table 2
-1
Gel-sol transition enthalpies from slope of van’t Hoff graphic ∆H (kJ mol ).
g
Bis(leuOH)
(S,S)-1
Bis(IleuOH)
Bis(ValOH)
(S,S)-3
Bis(PhAlaOH)
(S,S)-4
Bis(EthButOH)
(R,R)-6
Solvent
(S,S)-2
LEE
LİE
-
20,8
24,7
21,7
30,3
41,1
33,5
38,9
154,0
127,8
93,7
26,1
23,9
13,0
19,7
50,1
-
-
40,4
30,8
9,8
MEE
MİE
PEE
PİE
102,4
-
-
-
94,1
26,5
62,2
184,4
132,5
9

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3
.2. FTIR
Interactions between the ingredients used in gel formulations, such as Bis(PhAlaOH),
FAEs) organic fluid and ibuprofen were studied using FTIR spectroscopy. The FT-IR spectral
(
analysis of ibuprofen alone showed that the same principal peaks were observed in
Bis(PhAlaOH) gel at the same wave numbers without any change (See SI). All principal
characteristic bands of the drug were also observed in the respective formulations. These
findings were suggestive of the absence of any major incompatibility between Bis(PhAlaOH)
and the components employed in the preparation of the respective formulations, or of any
direct interactions between them.
3
.2.1. Temperature dependent FTIR investigations
In order to obtain further information on the organogelation mechanism, we measured
the FTIR spectra at various temperatures. To identify intermolecular interactions,
o
temperature dependent IR spectra of Bis(PhAlaOH) / LEE gel were investigated from 25 C to
o
1
40 C, as well as in the crystals of bis(phenylalanilol) derivatives BAOA, the corresponding
FTIR spectra were analyzed (Table 3).
Table 3
-
1
Temperature dependence of Selected FTIR bands [ in cm ] of Bis(PhAlaOH)/ LEE gel.
o
-1
-1
-1
-1
Temperature ( C)
Amide I cm
1653
Amide II cm
1522
-NH cm
3287
3287
3287
3289
3289
3293
-OH cm
3387
2
5
7
5
0
5
1653
1653
1652
1522
1518
3374
3378
3389, 3482
3392, 3552
3392, 3484, 3539
1
1
1
00
25
40
1518, 1500
1501
1653, 1682
1685 (1653 weak)
1499
-
1
In the (S,S)-4 gel spectra at room temperature, the NH bands at 3294 and 3296 cm and
-
1
those of amide-I at 1656 and 1654 cm correspond to the hydrogen-bonded NH and CO
o
functionalities of the oxalamide units, respectively. In the spectra of the solutions at 125 C,
-1
both the NH and amide-I bands shift to higher wave numbers (NH 3392 and 3387 cm , and
-
1
amide-I 1681 and 1679 cm ), indicating a disruption in the intermolecular hydrogen bonds
between the oxalamide units of the gelator molecules. At the same time, the broad, low-
-
1
intensity bands at 3552 cm that appear in the solution spectra can be assigned to non-
associated OH groups. These observations suggest that both the oxalamide and OH groups
are involved in intermolecular hydrogen bonding which stabilizes the gel-fiber organization.
Neither NH nor amide-I bands typical of non-hydrogen bonded species are observed in the
2
9
spectra of gels at room temperature. However, these non-hydrogen bonded bands, 3392,
-
1
-1
-1
3
398 cm (free NH bond); 1685 cm , 1501 cm (free amide I and amide II bond),
1
0

respectively, can be detected in the spectra recorded at elevated temperatures see fig. 5).
(
These observations strongly suggest that most of the gelator molecules are aggregated at
ACCEPTED MANUSCRIPT
room temperature. In the FTIR spectra of (S,S)-4, the different shoulder positions at 3378
a)
b)
o
Fig.5. Temperature dependent (25-140 C) FTIR spectra of Bis(PhAlaOH) / LEE gel. Shifting of wave numbers and
intensity changes by temperature increasing. a) amide I, amide II bands; b) NH, OH bands.
-
1
-1
and 3365 cm OH band as well as at the 3287 and 3289 cm NH amide I band and (1525 and
-
1
1
522 cm ) amide II bands might indicate that the oxalamide units are subject to different
hydrogen-bonding environments. Clear differences in the NH and amide I regions are
observed in the spectra of gels, depending on the temperature changes.
3
.3. SEM observation of the xerogels
It is well-known that the organogelators form an organogel through the construction of a
3
0
three-dimensional network by entanglement of self-assembled nanofibers. Such
nanostructures of organogelators can be observed by using an electron microscopic
technique. Fig.6 shows the field emission scanning electron microscope. (SEM) images
demonstrate the helical bundle formed by self – assembled nanofibers. The helical bundle
structure is formed by helical nanofibers. There are many paper and reviewer discussing el
3
1
chirality. The chiral information is directly translated from the molecular building blocs into
the nanoscale fibriller architectures. Here, it is obvious that similar results are obtained.
ig.6. Electron microscopic images of dried gel prepared from: benzyl oxalamide LEE gel.(5mg) Bis(PhAlaOH) gelator/ 1 mL
LEE.
1
1

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3
.4. The influence of FAE nature drug loading capacity of Bis(PhAlaOH)
The organogelation ability significantly depends on the nature of the amino alcohol
moieties attached to the oxalamide linker of BAOA bis(amino alcohol)oxalamide gelators;
especially compound (S,S)-4, Bis(PhAlaOH) gelator having a benzyl group, functions as a good
organogelator; has a high thermal stability and the lowest minimum gel concentrations
amongs all to be tested BAOA gelators in various FAEs (Table 1). For this reason, (S,S)-4 was
chosen as a drug carrier organogelator; and drug loading was tested . See Fig. 7.
LEE/Ibuprofen
LIE/Ibuprofen
MİE/Ibuprofen
PEE/Ibuprofen
Fig.7. Selected Ibuprofen loaded (S,S-4, Bis(PhAlaOH)) / FAE’s gels (3.5 mg S,S-4; 2.0 mg Ibuprofen in 1 mL FAE’s).
Up to 2.90 % Ib loading could be achieved without gel disruption. As shown in Table 4, drug
loading capacity increased with the increasing FAEs chain length for ethyl esters. But in the
case of isopropyl ester group, it is not dependent only FAEs chain length but also steric
factores may be dominant. Maximum loading capacity was obtained with LIE tested as a
solvent among FAE’s.
Table 4
Drug loading capacity of Bis(PhAlaOH) gelator depending nature of solvents (FAEs structure). 3.5 mg Bis(PhAlaOH) and 1 mL
FAEE (LEE, LIE, MEE, MIE, PEE, PIE). w drug weight, w gelator weight; w gel weight.
d:
g:
m:
Solvent
Max. Drug loading capacity
d
Max. w / wg
2
(
% w /w )x10
Ratio
2.86
5.14
6.85
7.42
2.86
4
g
m
LEE
MEE
PEE
LIE
MIE
PIE
1.14
2.04
2,68
2,90
1.16
1.60
3
.5.The influence of pH on the release of Ib
Fig. 8 shows the influence of the different pH buffers as receptors on the release of Ib
from the organogels formed by Bis(PhAlaOH). The release profiles of Ib are similar to those
shown in Fig. 8. As shown in Fig. 8, good linear correlations (correlation coefficients of 0.99)
were obtained from the plots of the release ratios of Ib against the square root of time.
1
2

ACCEPTED MANUSCRIPT
When the different pH buffers were used as receptors of Ib instead of water, the release
mechanism of Ib from the organogels followed Fickian diffusion control within given time.
Although the release ratios of Ib are clearly dependent on the pH values of buffer solution,
when pH is greater than 7, the pH values of the buffer solution seem to exert no significant
effect on the release of Ib. But in buffer solution of pH 5.5, due to the extremely low
solubility of Ib in water at acidic pH values, the release rate of Ib from the organogel
decreased; in this case acidic receiving medium, Ib releasing from the organogels is better
retained than an alkaline receiving medium. This can be explained by decreasing water
solubility of Ib in acidic receiving medium. Just the COOH is protonated so does not release.
1
1
20
00
pH=7.4
pH=7.0
pH=5.5
8
6
4
2
0
0
0
0
0
0
1
2
3
4
1
/2
t
(h)
5
4
4
3
3
2
2
1
1
0
5
0
5
0
5
0
5
0
pH=7.4
pH=7.0
pH=5.5
5
0
0
2
4
6
8
10
t (h)
1
/2
Fig. 8 Percentages of Ib remaining in the gel as a function of t (top plot a linear relationship is apparent) and Release
o
ratios (bottom plot) as a function of t in the case of various pH buffer solutions as receptor media at 25 C. The organogels
contained 2 mg/mL of Ib and 3.5 mg Bis(PhAlaOH) gelator in the 1 mL of LEE fluid formed by 0.23 w% of drug formulation
before release.
1
3

3
.6. The influence of solvent on the release of Ib
ACCEPTED MANUSCRIPT
In the case of fatty acid isopropyl esters, the release ratios of Ib are clearly dependent
on the FAE’s chain length Fig.9; the release ratios of Ib dramatically increased with
decreasing chain length. But in the case of fatty acid ethyl esters, the release ratios do not
affected by alkyl chain length. Besides the effect of ester alkyl groups of FAEs which have
same alkyl chain length, isopropyl esters are better than their ethyl ester.
Fig.9. Release ratios (left plot) and release kinetics (right plot; C : initial concentration of ibuprofen, C: remaining
0
concentration of Ib in the gel) of Ib from organogel formed by 0.4 w% of (S,S)-4 depending on various organic fluids at
o
constant pH (pH 7.4 buffer solutions as receptor ) at 25 C. The organogels contained 2 mg/mL of Ib and 3.5 mg
Bis(PhAlaOH) gelator in the 1 mL of organic fluids (PIE, LIE, MIE, LEE, MEE, PEE) formed by 0.23 w% of drug formulation
before release.
3
.7. The influence of the Bis(PhAlaOH) concentration on the release of Ib from
supramolecular organogel
Fig.10. shows the influence of Bis(PhAlaOH) concentration on the release of Ib from
supramolecular organogels. In these experiments,
and release experiments were
o
conducted at constant temperature (25 C). When the different Bis(PhAlaOH) concentration
were used as a gel matrix, the release profiles of Ib show typical sustained release
behavior. As shown in Fig.10, the release ratio of Ib from the organogels decreased with an
increase of Bis(PhAlaOH) concentration. The release ratios of Ib after 8 h were found to be,
6
5.4, 56.3, and 48.1 wt%, at 2, 3.5 and 7 mg / mL gelator concentrations respectively. This
result shows that the release of Ib can be controlled by
1
4

ACCEPTED MANUSCRIPT
Fig.10. Release profiles of Ib from the the organogel (LEE) (left plot) and percentages of Ib remaining in the gel as a function
1/2
of t (right plot, a linear relationship is apparent) and both of them depending on different Bis(PhAlaOH) concantrations at
o
2
5 C .
Bis(PhAlaOH) concentration. The release behavior of Ib (Fig.10) from supramolecular gel
network may be explained by the diffusion and motion of drug molecules in the organogel
system. As it is well known, organogelators self - assemble in organic fluid into fiber–like
aggregates. Furthermore, organogels with 3D structures can be formed by both physically
3
2
branched fibers (interconnected networks) and entangled fibers. In the present study, the
low release rates of drug molecules can be attributed to the presence of dense 3D networks
formed by increasing concentrations of Bis(PhAlaOH). In other words, the diffusion of Ib
3
3
must overcome more obstacles and use more zig-zag routes within the organogel.
When the amount of Ib remaining in the organogel was plotted against the square root of
time, a good linear correlation (correlation coefficients were 0.99) was found in accord with
3
4
the Higuchi equation. This linear relationship indicates that the release mechanism of Ib
35
from the organogels follows Fickian diffusion control within the given time range.
.8. The influence of Ib concentration on the release of Ib
3
Fig.11 shows the influence of the concentration of Ib on the release of Ib from
0
supramolecular organogels formed Bis(PhAlaOH) / LEE at 25 C. As the low region of Ib
concentrations, while the relase rate is fast but at high region, after a certain concentrations
the release rate remains unchanged.
1
5

ACCEPTED MANUSCRIPT
1
/2
o
Fig.11. Percentages of Ib remaining in the gel as a function of t , at different Ib concantrations, at 25 C. The gels
contained 2000 mg/L of Ib in LEE before release.
As discussed above, the release mechanism of Ib from the organogels was in accord with
Fickian diffusion control; generally, rate of controlled release depends only on the solute
concentration difference at both sides of the organogel / solution interface and on the
solute concentration within the organogel. If high concentrations of Ib disrupt fiber-like
aggregates of organogelator Bis(PhAlaOH), this results in partial collapse of 3D networks
within the organogel and leads to an increase in the amount of released Ib. For this reason,
even if a high drug load, due to the increased release rate, % wt of Ib remaining in the gel
matrix (100- % release) is nearly unchanged (seeFig.11).
As shown in Fig.12 the released drug quantity in the first 8 h period increases with
increasing drug loading quantity.
Fig.12. First 8 h period of released drug amount depending on drug loading quantity of Bis(PhAlaOH)/LEE gel
1
6

CONCLUSION
Organogels have emerged as a potential drug carrier system. In contrast to other lipid
ACCEPTED MANUSCRIPT
based system such as vesicular systems (liposome and noisome), organogel systems may
prove to have edge in terms of cheap raw materials and ease of preparation and most
importantly technological feasibility.
In this paper, we revealed organogelation properties of BOA gelators in pharmaceutical
fluids. Among these organogelators, bis-phenylglycinol oxalamide has no organogelation
ability in FAEs, while others reveal good gelation ability with the same solvents. The
organogelation ability significantly depends on the nature of amino alcohol part; especially
compound (S,S)-4 which has phenylalanilol group, functions as a good organogelator; has a
high stability and the lowest minimum gel concentrations in all tested gelation solvents.
Compouds 1, 2 and 3 which have isobutyl, sec-butyl and isopropyl groups respectively,
have low thermal stability due to sterically hindered branching alkyl groups. (S,S)-4 reveals
high thermal stability and good gelation properties toward all to be tested gelation solvents.
(S,S)-4 / FAEs gel network reveals via not only van der Waals interactions and hydrogen
bonding; and also additional stacking interaction between gelator molecules due to
benzylic groups at aminoalcohol moieties.
Supramolecular organogels formed from bis-(aminoalcohol) oxalamides were
prepared and used as a drug carrier for NSAID ibuprofen. The release ratios of Ib
from the organogels were clearly dependent on the pH values of the buffer solutions
used as receptor; and dependent on amino alcohol groups on the oxalamide linker.
Hence controllable release was closely linked with the structure of gelators and also
the organic fluids. Furthermore, the release ratios of Ib was dependent on the
concentration of gelator and also portion of drug (%w) in the gel matrix. Finally, these
observations indicate that bis(aminoalcohol) oxalamide gels can be used as delivery
vehicle for non-steroidal anti-imflammotory drug molecules and also show that the
release profiles for such systems can be fine-tuned by the correct choice of gelator-
FAE combination. On the other hand, BOA organogels as a drug delivery vehicle can
also become a viable alternative, to skin cancer in people. if anticancer agents are
delivered through them.
1
7

Good linear relationships between the released amount of Ib and the square root of time
ACCEPTED MANUSCRIPT
indicated that the release mechanism of Ib from the organogels was in accord with Fickian
diffusion control in the given time range. The entrapment of small drug molecules within a
LMWG gel can be achieved in a variety of simple ways, all of which can lead to rather high
loading. In this study, 2.90 % loading has been achieved without gel disruption with
Bis(PhAlaOH) / LIE as a gelator-FAE combination.
Conflict of interests
The authors declare that there is no conflict of interest regarding the publication of this paper.
Acknowledgements
We would like to thank The Scientific and Technological Research Council of Turkey (TUBITAK) for
financially supporting this research (Project No. 113Z142). And we extend our thanks to the Dicle
University, Research and Project Coordination for their support to our Project (No: 13-FF-73).
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