Fabrication of organogels achieved by prodrug-based organogelators of ketoprofen

Article abstract of DOI:10.1039/c4ra03688c

The treatment strategy of curing diseases using prodrugs of an anti-inflammatory drug is widespread. In the present study, we report on the synthesis of prodrugs of ketoprofen, consisting of a derivatization of ketoprofen and long hydrocarbon chain of fat

Full text of DOI:10.1039/c4ra03688c

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Fabrication of organogels achieved by prodrug-
based organogelators of ketoprofen
Cite this: RSC Adv., 2014, 4, 33286
*
Rahul R. Mahire, Deepika S. Agrawal, Devanand K. Patil and Dhananjay H. More
The treatment strategy of curing diseases using prodrugs of an anti-inflammatory drug is widespread. In the
present study, we report on the synthesis of prodrugs of ketoprofen, consisting of a derivatization of
ketoprofen and long hydrocarbon chain of fatty acids with diacylhydrazine linkage. The presence of an
acidic moiety in ketoprofen may lead to ulceration in the gastrointestinal tract that reduces the efficacy
of the drug with an increased adverse effect. The synthesis of prodrugs of ketoprofen involves the use of
fatty acids as a carrier and hydrazine as a spacer. Synthesized prodrugs were characterized by infrared,
1H-NMR and mass spectroscopy. The resulting prodrugs were found to be insoluble in water and
precipitated out in acetonitrile, hexane, benzene, and so on. The synthesized prodrugs are slightly
soluble in chloroform, methanol and ethanol and only form a gel like structure in carbon tetrachloride.
The resulting gels are referred as organogels and prodrugs are referred to as organogelators. The surface
morphology of the prepared organogels were studied by field emission-scanning electron microscopy
(FE-SEM) and transmission electron microscopy (TEM), and other spectral characteristics were also
investigated. FE-SEM and TEM images revealed that there were continuous elongated fiber-like
structures present that were in the nanometer size range. Gel–sol temperature profiles of the prepared
organogels were also studied using differential scanning calorimetry. The results from all these
techniques are presented and discussed from point of view of the use of the derivatives as prodrug
formulations. It is demonstrated that the prodrug containing the diacylhydrazine moiety has the ability to
form a gel.
Received 23rd April 2014
Accepted 11th July 2014
DOI: 10.1039/c4ra03688c
www.rsc.org/advances
shows some adverse effects because of the presence of an acidic
moiety in ketoprofen which causes ulceration in the stomach
with prolonged use and also reduces its bioavailability.5,6 It is
well documented that prodrugs increase solubility and
bioavailability of the parent drug.7 The ketoprofen–saccharide
conjugates and a polymeric prodrug can be synthesized
successfully by using enzymatic or chemo-enzymatic reactions
with biocompatibility and low toxicity.5,6
Many pharmaceutical chemists address drug delivery prob-
lems through use of prodrugs, gels, emulsion formulation, and
so on. The gels are intermediate states of matter containing
both solid and liquid components. Formation of gels requires a
continuous network which may be achieved from ber
enlargement or trapping the mobile phase. Gelation takes place
in organic media as a result of the binding forces between the
gelator, intermolecular hydrogen binding or metal coordination
bonds.8 The formation of gel is because of non-linear poly-
merization of the molecule and the degree of polymerization
depends upon the solute–solvent interactions. The structural
details of the gel includes the conformation of molecule, nature
and the extent of side-chains as well the solvent characteristic
and inter-molecular forces.9 Weak physical forces of attraction
such as van der Waals interaction, hydrogen bonding, and p–p
stacking are assumed to be responsible for the exibilities of
Introduction
Development of drugs with minimum side effects is a never
ending saga for pharmaceutical chemists. The prodrug concept
is emerging as a new strategy in the eld of drug delivery. Pro-
drugs provide sustainable release of a drug with efficient site
availability, and improved bioavailability with minimum side
effects.1 The prodrug concept is that there is an inert derivative
of the drug which is used to enhance the bioavailability and
solubility during administration of parent drug. A prodrug is
the bioreversible derivative of the parent drug, which changes
the physiochemical properties and the pharmacological proles
of a drug molecule.2 A synthetic strategy to design prodrugs
includes minimization of side effects with easy administration
of the parent drug. Non-steroidal anti-inammatory drugs
(NSAIDs) have limitations that are attributed to their ulcero-
genic side effects in the gastrointestinal tract and poor water
solubility.3 Ketoprofen is the NSAID widely used in the treat-
ment of tissue injuries and which diminishes inammation
associated various diseases by arresting prostaglandin
synthesis.4 An earlier pharmacological study of ketoprofen
School of Chemical Sciences, North Maharashtra University, Jalgaon-425 001, M. S.,
India. E-mail: dhmore@rediffmail.com; Fax: +91-257-2258403
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gels and their stability.10,11 These gels play an important role in
the polymer sciences, drug delivery, pharmaceuticals, food
industry, cosmetics, making athletic shoes, and so on.12 The
gels can be differentiated into hydrogels and organogels on the
basis of the solvent used for their preparation. Hydrogels are
prepared in water whereas organogels exist in organic solvents
of a low-medium and a low polarity. The microscopic frame-
work of the organogel is a branched network of interlocking
bers that improve transdermal drug delivery.13 Nowadays these
gel-like structures and the study of them are claimed to form a
sixth state of matter. Therefore many scientists are now engaged
in the study of the mechanisms involved in the nucleation and
growth of the gel network in a suitable solvent system.14 Yuk
et al.15 have reported a pH-sensitive drug delivery system using
an oil/water emulsion and also a hydrogen bonded complex gel
in water for the temperature sensitive drug delivery system.16
It is always a challenging task to design organogelators
because so many factors are known to govern their formation
such as steric effects, ability to gel, polarity, thermal stability,
and so on. Examples of the various organic building blocks that
can be utilized are: saccharides, nucleic acid, cholesterol
derivative, ureas, esters, amides, peptides, and so on.17 Biode-
gradable and biocompatible materials are used to prepare
gelators in order to avoid side effects for sustained release.18,19
Generally, fatty acids have been used to prepare organogels of
NSAIDs.20 We report on studies related to the synthesis of
prodrug-based organogelators containing long carbon chains
and hydrazine as a spacer. The use of hydrazine as an active
center containing carbon and nitrogen is responsible for the
physical and chemical properties of the hydrazines and they are
used for the synthesis of prodrug-based organogelators.
Scheme 1 Synthesis of prodrug-based organogelators. KPL: N0-(2-(3-
benzoylphenyl)propanoyl)tetradecanehydrazide, KPM: N0-(2-(3-ben-
zoylphenyl)propanoyl)tetradecanehydrazide, KPP: N0-(2-(3-benzoyl-
phenyl)propanoyl)palmitohydrazide, KPST: N0-(2-(3-benzoylphenyl)
propanoyl)stearohydrazide.
Table 1 Gelation study of organogelators in various solventsa
Solvents
KPST
KPP
KPL
KPM
Water
I
I
I
I
Chloroform
Methanol
Ethanol
Carbon tetrachloride
Acetonitrile
Hexane
Benzene
o-Xylene
m-Xylene
p-Xylene
n-Heptane
n-Octane
S
S
S
G
P
P
P
P
P
P
P
P
S
S
S
G
P
P
P
P
P
P
P
P
S
S
S
G
P
P
P
P
P
P
P
P
S
S
S
G
P
P
P
P
P
P
P
P
a
I: insoluble, P: precipitate, G: gel, S: soluble.
Result and discussion
Designing prodrug-based organogelators of ketoprofen
This gel formation is because of the intermolecular force of
attraction, which causes aggregation of molecules that promote
formation of gels having a well dened pattern of bers. Gel
formation was conrmed by inverting the glass vial and if no
gravitational ow was observed, then a gel had been formed.
Prepared organogelators do not aggregate in water, they
remain insoluble even aer prolonged heating. In chloroform,
methanol and ethanol organogelators were soluble but unable
to form gels, whereas in acetonitrile, hexane and the other
solvents tested (Table 1), organogelators were precipitated out.
It was found that in carbon tetrachloride, molecules of prodrug-
based organogelators were aggregated and formed a gel of
excellent quality.
The therapeutic efficacy of ketoprofen can be increased by
preparing its prodrug, which is of great importance for
contemporary drug delivery. Recently researchers have synthe-
sized a prodrug of ketoprofen, but there were problems in the
drug administration. We aimed to synthesize prodrugs of
ketoprofen that contained a long hydrocarbon chain followed
by incorporating diacylhydrazine linkage (Scheme 1) which may
cleaved to release the parent drug. The gel formation of the
synthesized prodrug was investigated. However, the gelation
occurs in organic solvents, thus the prepared prodrugs are
referred to as organogelators.
Gelation studies of prodrug-based organogelators
Synthesized prodrug-based organogelators were introduced to a
wide range of solvents (Table 1). An appropriate amount of
Gel–sol transition temperature (Tgel
)
organogelators were poured into different glass vials containing The gel–sol transition temperature (Tgel) is the temperature at
a particular amount of solvents (1–10% w/v). The solutions which the gel starts to melt and becomes a solution, this was
obtained were heated slowly to cause dissolution of the orga- investigated by a previously reported method.21 In organogels
ꢀ
nogelators, because as the heating period increases, the disso- prepared at 1–10% w/v, the Tgel occurs between 40–60 C and
lution of the organogelators increases. The resultant solutions aer 5% w/v the gels are nearly at the same Tgel (Fig. 1). The
were cooled at room temperature to visualize gel formation. concentration of organogelators were increased from 1% to 5%
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transmission electron microscopy (TEM). The images at a 5%
w/v concentration of KPST, KPP, KPM and KPL organogels show
a well dened pattern of long thinner bers having widths
between 1.03 mm and 145 nm (Fig. 3). In contrast FE-SEM
images obtained at a 1% w/v concentration exhibited no such
network of thin bers (Fig. 4). Therefore, it is clear that gels
obtained at a 5% w/v concentration are well aggregated and
form a better quality of gels than those obtained using 1% w/v
concentration. TEM images of organogels obtained at a 5%
w/v concentration are shown in Fig. 5, and the images reveal
that the prepared organogels have ber thickness of approxi-
mately 212 nm. However, ber thickness also varies up to 0.26
mm. FE-SEM and TEM images of KPST, KPP, KPM and KPL
organogels showing long, continuous, uniformly elongated
bers. The characterization suggested that organogels are
fabricated in a well dened network pattern. Thus, prodrug-
based organogelators assemble in a brillar network with a
well dened pattern. An increased length of organogelators
facilitates the formation of aggregates and also promotes
gelation.
Fig. 1 Gel–sol transition temperature of organogels prepared from
KPST, KPP, PKM, and KPL.
w/v for the gels tested, and it was observed that up to 5% w/v,
Tgel also rises and it remains approximately the same from
then onwards. This may be because of the length of the carrier
which affects the Tgel to a certain extent, because as the number
of carbons increases, the strength of the gel also increases.
Thus, it can be concluded that the long chain of the carbon is
responsible for the stability of the gels.
In differential scanning calorimetry (DSC) measurements,
when the gel was heated slowly, the temperature rises and at a
certain temperature, the gel melts suddenly exhibiting an
ꢀ
endothermic peak at 52.94 C. The enthalpy of transition from
gel to solution is at DH ¼ 126 J gꢁ1 calculated from the DSC
thermogram (Fig. 2). When the gel was cooled it shows an
exothermic peak at 47.26 C having DH ¼ ꢁ94.62 J gꢁ1. There-
ꢀ
fore, it can be concluded that organogels have a well-dened
thermoreversible sol–gel transition.
Fig. 3 FE-SEM images of organogels obtained at 5% w/v. (a) KPST
organogel; (b) KPP organogel; (c) KPM organogel; (d) KPL organogel.
Morphology of organogels
Surface morphology of all the organogels were studied by eld-
emission-scanning electron microscopy (FE-SEM) and
Fig. 4 FE-SEM images of organogels obtained at 1% w/v. (a) KPST
Fig. 2 DSC thermogram of KPST organogel.
33288 | RSC Adv., 2014, 4, 33286–33291
organogel; (b) KPP organogel; (c) KPM organogel; (d) KPL organogel.
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Fig. 7 Comparison of FT-IR spectra for KPST and the organogel of
KPST.
Fig. 5 TEM images of organogels obtained at 5% w/v. (a) KPST orga-
nogel; (b) KPP organogel; (c) KPM organogel; (d) KPL organogel.
1H nuclear magnetic resonance (1H-NMR) and Fourier
transforms infrared spectrophotometry (FT-IR) study
Experimental
Materials
The 1H-NMR spectra of organogels exhibits quite similar
features to that of its respective organogelators, even the
aromatic region does not indicate any shiing of signals (Fig. 6).
Therefore, it may be concluded that there is no p–p stacking
involved in the fabrication of the network. An FT-IR study
revealed that the amide bond of KPST had NH and CO
stretching at 3261 and 1739, 1705, 1668 cmꢁ1 and this was
attributed to presence of a non-hydrogen bonded amide group.
The FT-IR spectra of the KPST gel showed that the amide proton
is merged in the alkyl region and does not show sharp bands
because of the strong intermolecular hydrogen bonding,
whereas the amide carbonyl exhibits shis at 1696, 1654 and
1584 cmꢁ1. This clearly indicates that the two amide bonds are
participating in stronger intermolecular hydrogen bonding,
which results in aggregation of molecules and promotes gela-
tion. Thus, the organogels encompassing the parallel sheet
pattern of a brillar network, because of the hydrogen bonding
between the carbonyl group of the amide group of one molecule
with the amide group of another molecule (Fig. 7).
The Ketoprofen used in this study was a gi from Enaltech
Laboratories, Mumbai (M.S.), India. All the chemicals and
solvents used were of synthetic grade (SD Fine-Chem, Mumbai,
India). All solvents and chemical were used as obtained.
Synthesis of organogelators
The overall reaction scheme was adapted to synthesize a fatty
acid derivative of ketoprofen which is a prodrug-based orga-
nogelators and is shown in Scheme 1.
Synthesis of 2-(3-benzoylphenyl)propane hydrazide (a). To
the mixture of ketoprofen (0.0039 mole) and absolute ethanol
(10 ml), 1–2 ml of conc. H2SO4 was added dropwise with
constant stirring and the reaction mixture was reuxed. The
progress of the reaction was monitored using thin-layer chro-
matography (TLC). Aer completion of the reaction, the
hydrazine hydride (99.9%; 0.0058 mole) was added dropwise
with continuous stirring. Then the reaction mixture was
reuxed for few hours. The completion of the reaction was
checked using TLC. Aer completion of the reaction, the reac-
tion mixture was poured in to a crushed ice-water mixture. The
synthesized product was collected from the organic layer using
water as a phase transfer medium. The product in organic layer
was washed with brine solution, yielding a yellowish colored
solid product and the presence water and vaporized impurities
were removed by applying a vacuum at 60 ꢀC. The synthesized 2-
(3-benzoylphenyl)propanehydrazide (a) was puried by column
chromatography (hexane–ethyl acetate (2 : 8)).
Synthesis of fatty acid derivatives of 2-(3-benzoylphenyl)-
propanehydrazide as organogelator. An equimolar mixture of 2-
(3-benzoylphenyl)propanehydrazide (a) was dissolved in tetra-
hydrofuran (10 ml), and to this solution acyl chlorides of the
corresponding fatty acids were added. Then the reaction
mixture was stirred at room temperature. The progress of the
reaction was monitored using TLC. The separated solids were
collected by ltration and washed with cold water and puried
by column chromatography. The organogelators prepared were
Fig. 6 1H-NMR spectra for the aromatic region of (a) KPST gelator; (b)
KPST organogel.
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characterized using infrared, NMR, mass spectral studies, and
the detailed are given next.
N0-(2-(3-Benzoylphenyl)propanoyl)stearohydrazide (KPST). Yield:
86%, FT-IR (nmax/cmꢁ1): 3261 (NH); 2927 (alkyl CH); 1739 (CO of
1
ketone); 1708, 1668 (CO of amide). H-NMR (d ppm): 7.77 (3H,
m); 7.65 (3H, m); 7.47 (3H, m); 5.75 (2H, s); 3.56 (1H, q); 2.33 (2H,
m); 1.59 (3H, d); 1.50 (2H, m); 1.21–1.24 (28H, m); 0.87 (3H, m).
Mass m/z: 535 (M + 1) (C34H50N2O3).
N0-(2-(3-Benzoylphenyl)propanoyl)palmitohydrazide (KPP). Yield:
82%, FT-IR (nmax/cmꢁ1): 3226 (NH); 2920 (alkyl CH); 1735 (CO of
1
ketone); 1701, 1660 (CO of amide). H-NMR (d ppm): 7.77 (3H,
m); 7.51 (3H, m); 7.45 (3H, m); 5.75 (2H, s); 3.76 (1H, q); 2.34 (2H,
m); 1.62 (3H, d); 1.54 (2H, m); 1.21–1.24 (28H, m); 0.87 (3H, m).
Mass m/z: 507 (M + 1) (C32H46N2O3).
N0-(2-(3-Benzoylphenyl)propanoyl)tetradecanehydrazide (KPM).
Yield: 70%, FT-IR (nmax/cmꢁ1): 3226 (NH); 2922 (alkyl CH); 1737
(CO of ketone); 1704, 1662 (CO of amide). 1H-NMR (d ppm): 7.79
(3H, m); 7.61 (3H, m); 7.48 (3H, m); 5.79 (2H, s); 3.74 (1H, q);
2.34 (2H, m); 1.58 (3H, d); 1.51 (2H, m); 1.21–1.25 (28H, m); 0.87
(3H, m). Mass m/z: 479 (M + 1) (C30H42N2O3).
N0-(2-(3-Benzoylphenyl)propanoyl)tetradecanehydrazide (KPL).
Yield: 65%, FT-IR (nmax/cmꢁ1): 3210 (NH); 2924 (alkyl CH); 1737
(CO of ketone); 1712, 1666 (CO of amide). 1H-NMR (d ppm): 7.77
(3H, m); 7.58 (3H, m); 7.41 (3H, m); 5.70 (2H, s); 3.71 (1H, q);
2.33 (2H, m); 1.54 (3H, d); 1.50 (2H, m); 1.21–1.24 (28H, m); 0.86
(3H, m). Mass m/z: 551 (M + 1) (C28H38N2O3).
Fig.
8
Organogelators dissolve in the carbon tetrachloride: (a)
before gelation; (b) after gelation; (c) organogel at 60 ꢀC; (d) organogel
at 25 ꢀC.
Preparation of organogels
Organogels were prepared by the prodrug-based organogelators
by taking appropriate amounts of solvents and gelators (110%
w/v) in scintillation glass vials which were sealed with a screw
1
ꢀ
Fourier transform infrared spectrophotometry, H-nuclear
cap. These vials were heated up to 60–80 C until the gelators
magnetic resonance and mass spectroscopy measurements
were completely dissolved in the solvents. Then the vials were
cooled slowly to room temperature, and aer approximately 70–
80 min, a viscous gel was obtained for each particular solvent.
The formation of the organogel (Fig. 8b) was conrmed by
inverting the tube, and if no gravitational ow was observed on
inverting the tube, then a gel had been formed.
The synthesized organogelators were analyzed on a Perki-
nElmer Spectrum One spectrophotometer using a Nujol mull
1
sampling method. H-NMR spectra were recorded on a Varian
Mercury 300 MHz NMR, and scanned at 300 MHz deuterated
chloroform as solvent. Chemical shis were reported in ppm
and compared to tetramethylsilane as an internal standard. The
mass spectra were recorded on a Shimazdu LCMS-QP 8000 LC-
MS spectrometer.
Gel–sol transition temperature (Tgel
)
The gel to solution transition of the prepared organogels was
determined by using the ‘Inversion tube method’.21 In this
method, gels of 1–5% w/v gelators were placed in oven in such a
way that the upper side of vial faces downwards and the vial and
its contents were heated slowly. At a certain temperature, the gel
melts and ows downwards in the inverted vial and this point is
referred to as the gel–sol transition temperature.
Differential scanning calorimetry
DSC analysis of the prepared organogels was performed using a
PerkinElmer DSC-400 instrument. The weighed samples (10
mg) were placed in an aluminium pan and the samples were
ꢁ1
ꢀ
scanned from 0 ꢀC to 200 ꢀC at a heating rate of 10 C min
.
Conclusion
Field emission-scanning electron microscope
We have reported the synthesis of prodrugs of ketoprofen. In
many cases prodrugs are not supposed to reached the site of the
drug's action, however, they are required as a carrier. In the
present work we introduced a long carbon chain via a diac-
ylhydrazine linkage to the ketoprofen. The overall purpose of
this study is to design prodrugs of ketoprofen. The prepared
The prepared organogels were scanned using a Hitachi High
Technologies S-4800-II SEM with an accelerating voltage of 5000
V and the emission current was 10 100 nA.
Transmission electron microscopy
TEM of the samples was performed using an FEI-Tecnai-F20 prodrugs must be able to form gels, thus the gelation ability of
electron microscope operating at 10 000 kV. A small amount the synthesized prodrug was also studied. An excellent gel
of gel sample was placed on the copper grid, it was dried at quality, with the formation of a brillar network was observed
room temperature and directly observed under the TEM.
using carbon tetrachloride. Thus, the prodrugs prepared are
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referred to as prodrug-based organogelators. The resulting gels
have a good themoreversible sol–gel transition.
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Acknowledgements
The Authors are grateful to Prof. K. J. Patil for his valuable
suggestions and Enaltec Laboratories Mumbai for the gi of a
sample of ketoprofen.
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