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is published by the American Chemical Society. 1155 Sixteenth Street N.W.,Washington, DC 20036Published by American Chemical Society. Copyright © American Chemical Society.However, no copyright claim is made to original U.S. Government works, or worksproduced by employees of any Commonwealth realm Crown government in the courseof their duties.
Article
Fast Dissolving Oral Drug Delivery System based on ElectrospunNanofibrous Webs of Cyclodextrin/Ibuprofen Inclusion Complex Nanofibers
Asli Celebioglu, and Tamer UyarMol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.9b00798 • Publication Date (Web): 22 Aug 2019
Downloaded from pubs.acs.org on August 27, 2019
Just Accepted
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1
Fast Dissolving Oral Drug Delivery System based
on Electrospun Nanofibrous Webs of
Cyclodextrin/Ibuprofen Inclusion Complex
Nanofibers
Asli Celebioglu* and Tamer Uyar*
Department of Fiber Science & Apparel Design, College of Human Ecology, Cornell University,
Ithaca, NY, 14853, USA*Corresponding Authors: AC: [email protected]; TU: [email protected]
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ABSTRACT: In this study, the polymer-free electrospinning was performed in order to produce
cyclodextrin/ibuprofen inclusion complex nanofibers, which could have potentials as fast
dissolving oral drug delivery system. Ibuprofen is a poorly water-soluble nonsteroidal anti-
inflammatory drug, but, the water solubility of ibuprofen can be significantly enhanced by
inclusion complexation with cyclodextrins. Here, Hydroxypropyl-beta-cyclodextrin (HPβCyD)
was chosen both as a nanofiber matrix and host molecule for inclusion complexation in order to
enhance water solubility and fast dissolution of ibuprofen. Ibuprofen was inclusion complexed
with HPβCyD in highly concentrated aqueous solutions of HPβCyD (200 %, w/v) having two
different molar ratio; 1:1 and 2:1 (HPβCyD:ibuprofen). The HPβCyD/ibuprofen-IC (1:1)
aqueous solution was turbid having some undissolved/uncomplexed ibuprofen whereas
HPβCyD/ibuprofen-IC (2:1) aqueous solution was homogeneous and clear indicating that
ibuprofen was totally complexed with HPβCyD and become water soluble. Then, both
HPβCyD/ibuprofen-IC solutions (1:1 and 2:1) were electrospun into bead-free and uniform
nanofibers having ~200 nm fiber diameter. The electrospun HPβCyD/ibuprofen-IC nanofibers
were obtained as nanofibrous webs having self-standing and flexible character, which is
appropriate for fast dissolving oral drug delivery systems. Ibuprofen was completely preserved
during the electrospinning process and the resulting electrospun HPβCyD/ibuprofen-IC
nanofibers were produced without any loss of ibuprofen by preserving the initial molar ratio of
1:1 and 2:1 (HPβCyD:ibuprofen). X-ray diffraction (XRD) and differential scanning calorimetry
(DSC) measurements indicated the presence of some crystalline ibuprofen in
HPβCyD/ibuprofen-IC (1:1) nanofibers whereas ibuprofen was totally in amorphous state in
HPβCyD/ibuprofen-IC (2:1) nanofibers. Nonetheless, both HPβCyD/ibuprofen-IC (1:1 and 2:1)
nanofibrous webs have shown very fast dissolving character when contacted with water or when
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wetted with artificial saliva. In brief, our results revealed that electrospun HPβCyD/ibuprofen-IC
nanofibrous webs have potentials as fast dissolving oral drug delivery systems.
KEYWORDS: Hydroxypropyl-beta-cyclodextrin, poorly water-soluble drug, inclusion
complex, electrospinning, nanofibers, fast dissolving, oral drug delivery
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1. INTRODUCTION
Fast dissolving oral drug delivery systems are getting more attention in pharmaceutics.1-5
The fast dissolving oral drug delivery systems are prepared as films or strips made of edible and
water soluble hydrophilic biopolymeric materials that can rapidly dissolve in oral cavity and
therefore can deliver drugs, vitamins and refreshing flavor compounds.2,3 The fast dissolving oral
films will offer advantage to deliver active compounds within oral cavity without the need of
water for swallow, and therefore fast dissolving oral films can be alternative to tablets and
pills.1,2 The fast-dissolving oral films containing drugs and bioactive compounds that can rapidly
dissolve or disintegrate in the oral cavity would offer great advantage in terms of high efficiency
absorption, enhancement of solubility, release, and bioavailability of such active agents.
However, most of the drug molecules and bioactive compounds are quite hydrophobic and are
not water-soluble or have very limited water solubility. Therefore, fast dissolving oral films are
often prepared with hydrophilic polymers such as gelatin, starch, carboxymethyl cellulose
(CMC), hydroxypropyl cellulose (HPC), pectin, alginate, chitosan, pullulan,
polyvinylpyrrolidone (PVP), polyethylene glycol (PEO), polyvinyl alcohol (PVA).4 The most
common technique for production of fast dissolving oral films is by film casting or hot melt
extrusion where active compounds are dispersed and encapsulated within hydrophilic
biopolymeric matrices.5 The fast dissolving oral films should have certain mechanical integrity
not be damaged during handling and transportation, yet, they should properly disintegrate in the
mouth. Therefore, the fast dissolving oral films should be mechanically strong and yet, they
should be soft, elastic and flexible.6 Recently, the use of electrospinning technique is also shown
to be a very promising approach for developing controlled drug delivery systems7-9 and fast
dissolving nanofibrous mats in pharmaceutics.10,11
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Lately, electrospun nanofibrous materials are gaining prominent interest in bio-
applications due to their very large surface area and highly porous characteristics along with their
soft and flexible nature.9 The electrospinning technique allows producing self-standing
nanofibrous mats and such nanofibrous mats do possess adequate mechanical integrity to be
proper candidates for fast dissolving oral delivery systems.11,12 The encapsulation of drugs and
bioactive agents within the nanofiber matrix is straightforward where the mixture of hydrophilic
biopolymer and active agents are prepared in common solution and thereafter the polymer/active
agent solutions are electrospun into nanofibrous mats. Typically, single nozzle electrospinning
setup is used since it is a very simple and versatile setup to produce functional nanofiber matrix
incorporating drugs or other bioactive agents. Moreover, the electrospinning of multiple-fluids is
also possible by using advanced nozzle systems such as, core-shell electrospinning13-15, side-by-
side electrospinning16 and tri-axial electrospinning17 in order to produce functional nanofibrous
materials for drug delivery systems. The production of electrospun nanofibrous materials
containing drugs or bioactive molecules can be done on a much larger scale, which makes this
technique practical for industrial applications.18
The electrospinning of nanofibers incorporating drugs has shown to be a very promising
approach for developing fast dissolving nanofibrous mats for oral drug delivery.11,12,15,18-25 The
self-standing electrospun nanofibrous mats made of hydrophilic polymeric nanofibers
incorporating bioactive agents having very large surface area and highly porous structure would
readily dissolve with water contact, and therefore such nanofibrous mats can be ideal candidates
for fast dissolving oral drug delivery systems. For instance, electrospun nanofibrous mats
encapsulating various drug molecules have been developed by using water-soluble hydrophilic
polymeric matrix such as polyvinylpyrrolidone (PVP)21,23, hypromellose24, hydroxypropyl
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methylcellulose (HPMC)25, gelatin19,22,26, poly (vinyl alcohol) (PVA)27, Eudragit L-10020, etc.
Recently, we have also shown that electrospun nanofibrous mats of polymer-free cyclodextrin
inclusion complex nanofibers incorporating drugs (e.g., sulfisoxazole28, paracetamol12) have fast
dissolving character. Besides being a nanofibrous carrier matrix for active agents, cyclodextrins
are highly water-soluble and significantly improve the water solubility of hydrophobic drug
molecules and bioactive agents by inclusion complexation. Therefore, such fast dissolving
electrospun nanofibrous webs produced from cyclodextrin inclusion complexes would be
suitable for fast dissolving oral delivery in pharmaceutics and nutrition, etc.
The use of cyclodextrins (CyDs) is very common in pharmaceutics since drug molecules
become highly water soluble with cyclodextrin inclusion complexation and such CyD/drug
inclusion complex systems can also enhance the bioavailability, stability and shelf-life of the
drug molecules.29-31 CyDs are doughnut-shaped molecules of cyclic oligosaccharides which are
produced from enzymatically hydrolyzed starch by the action of cyclodextrin
glucosyltransferase. Due to their unique molecular structure having truncated cone-shaped
hydrophobic cavity, CyDs act as host for variety of molecules including drugs to form non-
covalent host-guest type inclusion complexes. CyDs are classified as GRAS (Generally
Recognized as Safe) by the U.S. Food and Drug Administration (FDA) and CyDs are already
being used in variety of drug and food formulations for the solubility increase, protection,
masking the odor and bitter taste and the controlled/sustained delivery of these active agents.29,32
Functional electrospun nanofibers have been developed by encapsulating CyD/drug inclusion
complexes within biopolymeric nanofiber matrix for the purpose of sustained/controlled release
of drugs33-36 or fast dissolving drug delivery systems.19,33 The polymer-free electrospinning of
CyD/drug inclusion complexes without using any polymeric matrix has also been shown to
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develop fast dissolving nanofibrous materials.12,18,28,37,38 Although electrospinning of nanofibers
from pure CyD/drug inclusion complex systems12,18,28,37-39 without using a polymeric matrix is
more challenging compared to electrospinning of polymeric systems, recently it has been shown
that electrospinning technique could produce high amount of CyD/drug inclusion complex
nanofibrous materials (e.g., voriconazole/sulfobutylether-β-cyclodextrin) that can be alternative
to freeze drying method.18
Ibuprofen (2-(4-Isobutylphenyl)propanoic acid) is one of the common nonsteroidal anti-
inflammatory drug that is generally used for reducing fever and treat pain or inflammation
caused by headache, migraines, toothache, back pain, arthritis, menstrual cramps, etc. Ibuprofen
is a poorly water-soluble drug, yet, it has been shown that inclusion complexation with CyDs
significantly improve the water solubility of ibuprofen.40-42 Ibuprofen can form 1:1 molar ratio
(Ibuprofen:CD) with β-cyclodextrin (β-CyD)40-42 and β-CyD derivatives40-42 such as methyl-β-
CyD, hydroxyethyl-β-CyD, and hydroxypropyl-β-CyD. Studies related to encapsulation of
ibuprofen within polymeric electrospun nanofiber matrix for controlled released of ibuprofen43-48
or fast-dissolution of ibuprofen23,49 were also reported. Typically, biodegradable polymeric
electrospun nanofiber matrices are used for the controlled released of ibuprofen43-48, on the other
hand, water soluble hydrophilic polymers are chosen for the fast dissolving nanofibrous webs.19-
27 Studies related to electrospun nanofibrous webs containing CyD/drug inclusion complexes
have shown that CyDs are very effective to increase the solubility of drug molecules and also
control the release of drugs when compared to same nanofibrous webs containing only drug
molecules without CyDs.14,33-35 Very recently, it has been reported that electrospun nanofibers of
poly-ɛ-caprolactone (PCL) containing CyD(α-CyD and β-CyD)/ibuprofen has been studied as a
controlled drug delivery system.50 Nonetheless, to the best of our knowledge, there is no study
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related to fast dissolving nanofibrous webs based on polymer-free CyD/ibuprofen electrospun
nanofibers. Hydroxypropyl-beta-cyclodextrin (HPβCyD) is a highly water soluble modified CyD
type which is very suitable for drug formulations for solubility enhancement of hydrophobic
drugs,29 in addition, HPβCyD is one of common CyD type which can be easily electrospun into
nanofibers by electrospinning without the need of using a carrier polymer matrix.12 On the other
hand, ibuprofen is one of most widely used drug but it is a poorly water-soluble drug which
suffers from its low solubility. The favorable inclusion complex formation and proper size-match
between ibuprofen and βCyD/derivates and the solubility enhancement of ibuprofen with CyD
inclusion complexation were already reported in the previous studies.40-42 Here, we have
produced fast dissolving nanofibrous webs from HPβCyD/ibuprofen inclusion complexes by
electrospinning technique without using any polymeric additive. Ibuprofen was complexed with
HPβCyD by two different molar ratios (1:1 and 2:1, HPβCyD:ibuprofen), and the structural
characteristics and properties of these HPβCyD/ibuprofen inclusion complex nanofibers were
investigated by using proper characterization techniques. It is also important to note that the
electrospinning was performed from aqueous solutions of HPβCyD/ibuprofen inclusion complex
which has a great advantage since ibuprofen become water soluble by HPβCyD. Therefore, it is
possible to use only water for the electrospinning of HPβCyD/ibuprofen inclusion complex
nanofibers whereas toxic organic solvents are used to dissolve polymeric matrix and
hydrophobic drugs for the electrospinning of polymer/drug based fast dissolving nanofibers.11,15
2. EXPERIMENTAL SECTION
2.1. Materials. Ibuprofen (97-103%, Spectrum), deuterated dimethylsulfoxide (d6-
DMSO, deuteration degree min. 99.8% for NMR spectroscopy, Cambridge Isotope) and
chemicals for buffer; sodium phosphate dibasic heptahydrate (Na2HPO4, 98.0-102.0%, Fisher
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Chemical), potassium phosphate monobasic (KH2PO4, ≥99.0%, Fisher Chemical), sodium
chloride (NaCl, >99%, Sigma Aldrich) and o-phosphoric acid (85% (HPLC), Fisher Chemical)
were obtained commercially and used without further purification. Hydroxypropyl-beta-
cyclodextrin (HPβCyD) was kindly donated by Wacker Chemie AG (USA). The high-quality
distilled water was used from the Millipore Milli-Q ultrapure water system.
2.2. Electrospinning of HPβCyD and HPβCyD/Ibuprofen-IC nanofibers.
2.2.1. Preparation of electrospinning solutions. Hydroxypropyl-beta-cyclodextrin
(HPβCyD) was completely dissolved in distilled water by 200% (w/v) solid concentration. Then,
ibuprofen was added to the clear HPβCyD solutions to get 1:1 and 2:1 HPβCyD:ibuprofen molar
ratios, separately. The HPβCyD/ibuprofen mixtures were stirred at room temperature for 24 hour
to form inclusion complexes. After 24 hour of mixing, 1:1 and 2:1 HPβCyD/ibuprofen systems
resulted in turbid and clear solutions, respectively. The comparative studies were performed with
pristine HPβCyD nanofibers; therefore 200% (w/v) concentrated pure HPβCyD solution was
prepared in distilled water as well for the electrospinning.
2.2.2. Electrospinning process. HPβCyD and each HPβCyD/ibuprofen inclusion complex
solution (1:1 and 2:1, HPβCyD:ibuprofen) was placed in 1 mL syringes fitted with 27 G
(outer/inner diameter; 0.4 mm/0.2 mm) metal needle, separately. The loaded syringe was placed
onto the syringe pump (New Era, USA) which ensured the flow rate of 0.5 mL/h solution during
the electrospinning process. The high voltage power supply (EPR series, Matsusada, Japan) was
used at a voltage of 15 kV, and the nanofibers were deposited on aluminum foil sheet that was
wrapped to a grounded metal collector at a distance of 15 cm from the tip of the needle. The
electrospinning process was carried out in an enclosed Plexiglass, which was positioned inside
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the fume cabinet. The ambient humidity and the temperature were recorded as 55% and 20 oC,
respectively. The electrospun nanofibers produced from 1:1 molar ratio of HPβCyD:ibuprofen
and 2:1 molar ratio of HPβCyD:ibuprofen inclusion complex solutions and pristine HPβCyD
solution were denoted as HPβCyD/ibuprofen-IC (1:1) nanofibers, HPβCyD/ibuprofen-IC (2:1)
nanofibers and HPβCyD nanofibers, respectively. Additionally, the physical mixture of
HPβCyD/ibuprofen (1:1) system was prepared for comparison. The pristine HPβCyD
nanofibrous web (~25 mg) was homogenously blended with ibuprofen powder (~3.5 mg) to
obtain HPβCyD/ibuprofen (1:1) physical mixture.
2.3. Characterization of Samples.
2.3.1. Morphological analysis. The surface morphology of HPβCyD/ibuprofen-IC (1:1)
nanofibers, HPβCyD/ibuprofen-IC (2:1) nanofibers and HPβCyD nanofibers was evaluated using
scanning electron microscope (SEM, Tescan MIRA3, Czech Republic). Prior the examination,
samples were fixed to carbon tapes which were stacked onto SEM stubs. Then, samples were
sputtered with thin layer of Au/Pd to render them electrically conductive. Images were taken at
the working distance of 10 mm and the accelerating voltage of 12 kV. ImageJ software was used
to calculate the average fiber diameter (AFD) by measuring the size of approximately 100 fibers.
The two main parameters influencing the morphology of nanofibers; conductivity and
viscosity were also determined as a part of this study. The conductivity of HPβCyD/ibuprofen-IC
and HPβCyD solutions were determined by conductivity-meter (FiveEasy, Mettler Toledo, USA)
at room temperature. The viscosity of the same solution systems was measure by rheometer (AR
2000 rheometer, TA Instrument, USA) equipped with 20 mm cone/plate accessory (CP 20−4
spindle type, 4o) under the shear rate range of 0.01-1000 s-1 at 22 oC.
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2.3.2. 1H-NMR analysis. Proton nuclear magnetic resonance (1H-NMR) spectra were
recorded by nuclear magnetic resonance spectrometer (Bruker AV500) with autosampler at 25
oC. The 1H-NMR was utilized to calculate the molar ratio between ibuprofen and HPβCyD in
HPβCyD/ibuprofen-IC nanofibers. Ibuprofen powder, HPβCyD nanofibers and
HPβCyD/ibuprofen-IC nanofibers were dissolved in DMSO‑d6 at the 30 g/L sample
concentration. 1H-NMR spectra were scanned 16 times for each sample. Mestranova software
was applied to get the integration of chemical shifts (δ, ppm). Then, the discrete peaks of
HPβCyD (-CH3; 1.03 ppm) and ibuprofen (aromatic protons; 7.2-7.5 ppm) were taken into
account to calculate the molar ratio of HPβCyD:ibuprofen in HPβCyD/ibuprofen-IC nanofibers.
2.3.3. FTIR analysis. The Fourier transform infrared (FTIR) spectra of ibuprofen powder,
HPβCyD nanofibers and HPβCyD/ibuprofen-IC nanofibers were obtained by Attenuated total
reflectance Fourier transform infrared (ATR-FTIR) spectrometer (PerkinElmer, USA). Each
spectrum (64 scan) was recorded between 4000 and 600 cm−1 at a resolution of 4 cm−1.
2.3.4. Thermal behavior analysis. Thermogravimetric analyzer (TGA, Thermal Analyzer
Q500, TA Instruments, USA) and differential scanning calorimeter (DSC, Thermal Analyzer
Q2000, TA Instruments, USA) were operated to investigate the thermal characteristic of the
samples. TGA measurements were carried under nitrogen atmosphere. The samples placed onto
platinum TGA pan were heated from room temperature to 600 °C at a heating rate of 20 °C/min.
For DSC analyses, samples were sealed into Tzero aluminum pan, and heated at a flow rate of 10
oC/min from 0 oC to 250 oC under nitrogen atmosphere.
2.3.5. XRD analysis. X-ray diffraction (XRD) patterns of ibuprofen powder, HPβCyD
nanofibers, HPβCyD/ibuprofen-IC nanofibers and HPβCyD/ibuprofen (1:1) physical mixture
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were recorded by powder X-ray diffractometer (Bruker D8 Advance ECO) by applying Cu-Kα
radiation. The samples were examined for the angles 2ϴ between 5o and 30o. The voltage and
current were set to 40 kV and 25 mA, respectively.
2.4 Pharmacotechnical properties of HPβCyD/ibuprofen-IC nanofibers. Phase
solubility profile of ibuprofen was investigated according to method reported by Higuchi and
Conners.51 A fixed amount of ibuprofen exceeding its solubility and HPβCyD with an increasing
concentration (0-10 mM) were weighed into a glass vials to which were added 5 mL water. The
vials were sealed and shaken for 24 h on incubator shaker (Fisherbrand) at 25 oC and 450 rpm,
shielded from the light. After equilibrium for 1 day, the suspensions were filtered with 0.45 µm
PTFE filter. The aliquot from each vial was measured using UV-Vis spectroscopy (PerkinElmer,
Lambda 35) to determine the amount of ibuprofen dissolved. The experiments were performed in
triplicate (n=3), the results were averaged and used to calculate the binding constant from the
following equation;
𝐾𝑠 =𝑠𝑙𝑜𝑝𝑒
𝑆𝑜 (1 ― 𝑠𝑙𝑜𝑝𝑒)
where S0 is the intrinsic solubility of ibuprofen in the absence of HPβCyD. UV-Vis spectroscopy
was also used to indicate the solubility enhancement of ibuprofen which is encapsulated in
inclusion complex nanofibers. For this purpose, 2 mM ibuprofen powder and
HPβCyD/ibuprofen-IC nanofibers that include the same amount of ibuprofen were stirred in
distilled water for 24 h. Afterwards, solutions were filtered by 0.45 µm PTFE filter and their UV-
Vis absorbance were measured in the range of 240–290 nm.
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For the dissolution test, ibuprofen (~5 mg), HPβCyD/ibuprofen-IC (1:1) (~38 mg) and
HPβCyD/ibuprofen-IC (2:1) (~72 mg) nanofibrous webs having the equivalent ibuprofen content
were weighted into glass vials. In order to follow the dissolution, a video was recorded
concurrently with the addition of distilled water (3 mL) into vials. Bi et al. reported a method at
which the physiological conditions under the surface of a moist tongue were simulated.52 Here,
the disintegration profiles of HPβCyD/ibuprofen-IC nanofibrous webs were examined with
slightly modified version of this technique. A proper size of filter paper was located in plastic
petri dishes (10 cm), and then they were wetted with 10 mL of artificial saliva (2.38 g Na2HPO4,
0.19 g KH2PO4 and 8 g NaCl were dissolved in 1 L distilled water, pH was adjusted to 6.8 by the
addition of phosphoric acid). After excess saliva was completely removed from the petri dishes,
a piece of HPβCyD/ibuprofen-IC nanofibrous web was placed at the center of the filter paper.
The time required for the disintegration of HPβCyD/ibuprofen-IC nanofibrous webs was
recorded as video.
3. RESULTS AND DISCUSSION
3.1. Electrospinning of HPβCyD and HPβCyD/Ibuprofen-IC Nanofibers. The
aqueous solutions of HPβCy/ibuprofen-IC having molar ratio of 1:1 and 2:1
(HPβCyD:ibuprofen) were prepared by using very high concentration of HPβCyD (200%, w/v)
(Figure 1). Such high concentration of HPβCyD is needed for the polymer-free electrospinning
of CyD solutions since high content of CyD aggregates in highly concentrated solution facilitate
the fiber formation during the electrospinning process.53,54 HPβCyD can form 1:1
(HPβCyD:ibuprofen) inclusion complex with ibuprofen in diluted solutions.40,42 Hence, we first
prepared the aqueous solution of HPβCy/ibuprofen-IC (1:1), but this solution was turbid due to
the presence of some uncomplexed/undissolved ibuprofen (Figure 2b). This is possibly because
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of the very high concentration (200%, w/v) and high viscosity of HPβCyD solution in which
ibuprofen molecules couldn’t interact efficiently with HPβCyD cavity to form 1:1 complexation,
and therefore some ibuprofen molecules remained uncomplexed/undissolved. Then, we doubled
the amount of HPβCyD, and prepared the aqueous solution of HPβCy/ibuprofen-IC (2:1). The
HPβCyD/ibuprofen-IC aqueous solution having 2:1 ratio was clear and homogeneous indicating
that ibuprofen was totally dissolved by inclusion complexation with HPβCyD (Figure 2c).
Figure 1. The chemical structure of ibuprofen and HPβCyD. The schematic representation of
inclusion complex formation between ibuprofen and HPβCyD molecules, and the
electrospinning of HPβCyD/ibuprofen-IC nanofibers.
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Figure 2. The photographs of electrospinning solutions and the resulting electrospun nanofibrous
webs, and the representative SEM images. (a) pure HPβCyD nanofibers (b) HPβCyD/ibuprofen-
IC nanofibers (1:1) and (c) HPβCyD/ibuprofen-IC (2:1) nanofibers.
The electrospinning of both HPβCyD/ibuprofen-IC aqueous solutions having 1:1 and 2:1
ratio was carried out in order to produce HPβCyD/ibuprofen-IC nanofibers (Figure 1). The
electrospinning of pure HPβCyD nanofibers without ibuprofen was also performed for
comparative studies. Figure 2a-c displays SEM images of the electrospun HPβCy/ibuprofen-IC
nanofibers (1:1 and 2:1) and the pure HPβCyD nanofibers. Under the optimized electrospinning
conditions/parameters, uniform nanofibers with bead-free morphology were obtained from
HPβCyD/ibuprofen-IC (1:1 and 2:1) and the pure HPβCyD systems. The average fiber diameter
of HPβCy/ibuprofen-IC (1:1) nanofibers, HPβCy/ibuprofen-IC (2:1) nanofibers and pure
HPβCyD nanofibers was measured as 180±95 nm, 210±55 nm and 215±65 nm, respectively
(Table 1). The same concentration of HPβCyD (200%, w/v) was used for the preparation of
inclusion complex and pure HPβCyD aqueous solutions. The viscosity of these solutions was in
the range of ~1.2-1.5 Pa•s and the conductivity of the solutions are in the range of ~35-45 µS/cm
(Table 1). The viscosity and the conductivity of the HPβCyD/ibuprofen-IC and pure HPβCyD
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aqueous solutions were not very different from each other, and therefore the average fiber
diameter of the resulting electrospun nanofibers from inclusion complexes and pure HPβCyD
systems were similar to each other. Nevertheless, the presence of ibuprofen caused a decrease in
viscosity but the solution conductivity was increased a bit, therefore, thinner fibers were
produced from inclusion complex systems compared to pure HPβCyD system. The viscosity of
the HPβCyD/ibuprofen-IC (1:1) solution was lower and its conductivity was slightly higher than
the HPβCyD/ibuprofen-IC (2:1) solution, so, the electrospinning of HPβCyD/ibuprofen-IC (1:1)
system resulted in nanofibers with slightly thinner diameter. These observations are well
correlated with the literature findings, where the electrospinning of lower viscosity and higher
conductivity solutions yielded thinner fibers due to more stretching of the jet during the
electrospinning process.55,56 More importantly, the electrospun HPβCyD/ibuprofen-IC nanofibers
were obtained as nanofibrous webs having self-standing and flexible character (Figure 2b-c),
which could be very appropriate for fast dissolving oral drug delivery systems.
Table 1. The solution properties and the fiber diameters of resulting electrospun nanofibers
Sample Molar ration of HPβCyD:ibuprofen
Viscosity(Pa•s)
Conductivity(µS/cm)
Average fiber diameter (nm)
HPβCyD - 1.533 36.3 215±65HPβCyD/ibuprofen-IC (1:1) 1:1 1.192 45.9 180±95HPβCyD/ibuprofen-IC (2:1) 2:1 1.380 44.3 210±55
3.2. Structural Characterization of HPβCyD and HPβCyD/Ibuprofen-IC
Nanofibers. The initial molar ratios between HPβCyD and ibuprofen in HPβCyD/ibuprofen-IC
solutions were 1:1 and 2:1, but after the electrospinning, the molar ratio of HPβCyD:ibuprofen
may change depending on the encapsulation efficient during the electrospinning process. Hence,
1H-NMR analysis was performed to determine the molar ratio between HPβCyD and ibuprofen
in electrospun HPβCyD/ibuprofen-IC nanofibers. The 1H-NMR technique enables the calculation
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of molar ratio by using the proportion of the integrated peaks of ibuprofen and HPβCyD. For
both HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1) nanofibers, the –
CH3 protons of HPβCyD at 1.03 ppm and aromatic protons of ibuprofen at 7.2-7.5 ppm were
used for the calculations (Figure 3).57 The designated peaks of ibuprofen at 7.2-7.5 ppm and
HPβCyD at 1.03 ppm are quite proper for the calculations, because these peaks are not
overlapped with the other peaks of both ibuprofen and HPβCyD (Figure 3). The initial molar
ratio for HPβCyD/ibuprofen-IC solutions was prepared as 1:1 and 2:1 (HPβCyD:ibuprofen) prior
to electrospinning, and it is important to have the same or similar loading of ibuprofen after
electrospinning in order to achieve high yield of drug encapsulation for HPβCyD/ibuprofen-IC
nanofibers. The 1H-NMR analysis revealed that the molar ratio of HPβCyD/ibuprofen-IC (1:1)
nanofibers and HPβCyD/ibuprofen-IC (2:1) nanofibers was determined as ~1:1 and ~2:1
(HPβCyD:ibuprofen), respectively. It can be concluded from these results that, ibuprofen was
completely preserved during the electrospinning and the resulting electrospun
HPβCyD/ibuprofen-IC nanofibers were produced without any loss of ibuprofen having the initial
molar ratio of 1:1 and 2:1 (HPβCyD:ibuprofen). As it will be discussed later, the XRD and DSC
analyses revealed that there is some uncomplexed ibuprofen in case of HPβCyD/ibuprofen-IC
(1:1) nanofibers. Yet, ibuprofen is not a volatile compound and the DMSO-d6 used for NMR
measurement could dissolve the uncomplexed ibuprofen in the nanofiber matrix, therefore the
exact molar ratio of 1:1 was calculated from 1H-NMR of HPβCyD/ibuprofen-IC (1:1)
nanofibers. To conclude, there was almost no loss of ibuprofen during the electrospinning
process and during the storage of the HPβCyD/ibuprofen-IC nanofibers. This confirms that
electrospinning is a very efficient encapsulation technique where the formulation of
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HPβCyD/ibuprofen-IC nanofibers can be effectively adjusted along with the predetermined
ibuprofen content.
Figure 3. 1H-NMR spectra of (a) pure ibuprofen, (b) pure HPβCyD nanofibers, (c)
HPβCyD/ibuprofen-IC (1:1) nanofibers and (d) HPβCyD/ibuprofen-IC (2:1) nanofibers. The 1H-
NMR spectra were recorded by dissolving the samples in DMSO-d6. The characteristic peaks of
ibuprofen and HPβCyD are highlighted with yellow and purple color, respectively.
The existence of ibuprofen in the HPβCyD/ibuprofen-IC nanofibers was also proved
using FTIR technique. FTIR is an expedient technique to investigate the formation of inclusion
complexes between CyD and guest molecules in which FTIR spectrum may show the
disappearance, attenuation, broadening and/or shifts for the characteristic absorption peaks of
guest molecules upon interaction within CyD cavity.58,59, Figure 4 presents the FTIR spectra of
pure ibuprofen powder, HPβCyD nanofibers and HPβCyD/ibuprofen-IC nanofibers. The broad
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and noticeable stretching peak exists between 3000 and 3600 cm−1 is the characteristic of the –
OH groups located at the primary and secondary hydroxyl groups of HPβCyD.12,28 In addition,
the vibrations of coupled C–C/C–O stretching and antisymmetric C–O–C glycosidic bridge
stretching are apparent around 1020 and 1150 cm−1 region.12,28 This region hardly gives evidence
about the inclusion complexation because the higher content of CyD in the inclusion complex
formulation cause significant overlapping and so the masking of characteristic peaks of
ibuprofen. On the other hand, the strong absorption band of ibuprofen displaying at 1706 cm-1
corresponds to the carbonyl stretching (C=O) was recorded for pure ibuprofen and this peak was
also observed for HPβCyD/ibuprofen-IC nanofibers (Figure 3b).60,61 The presence of C=O
stretching confirms the existence of ibuprofen in HPβCyD/ibuprofen-IC nanofibers.
Additionally, C=O peak of ibuprofen is reduced in intensity and shifts from 1706 cm-1 to 1720
cm-1 for HPβCyD/ibuprofen-IC nanofibers (Figure 4b). This agrees with the previous reports
indicating that the intermolecular hydrogen bonding existing through the ibuprofen crystals
breakdown and the C=O groups of ibuprofen form hydrogen bonds with hydroxyl groups of
CyD.40,60 Another ibuprofen stretching band, which is not as strong as carbonyl group, observed
at 1507 cm-1 also shifted to 1514 cm-1 and has reduced intensity in HPβCyD/ibuprofen-IC
nanofibers due to the interaction with HPβCyD cavity. In short, the FTIR study confirms the
presence of ibuprofen in HPβCyD/ibuprofen-IC nanofibers and suggests that the ibuprofen is in
the state of inclusion complexation with HPβCyD cavity.
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Figure 4. (a) The full and (b) expanded range FTIR spectra of pure ibuprofen powder, pure
HPβCyD nanofibers, HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1)
nanofibers.
XRD is a useful technique to confirm the inclusion complex formation between CyD and
guest molecules. The alteration in XRD patterns of inclusion complex components such as;
disappearance of crystalline peaks, shifts, decrease in the peak intensity or appearance of new
peaks mostly due to the amorphization and/or complexation.58,59 Figure 5a depicts the XRD
patterns of pure ibuprofen powder, HPβCyD nanofibers, HPβCyD/ibuprofen-IC nanofibers and
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HPβCyD/ibuprofen (1:1) physical mixture. Pure ibuprofen displays a crystalline structure with
the sharp diffraction peaks at 6.1°, 16.6° and 22.3°. The diffraction pattern of HPβCyD
nanofibers has two broad halos at 10.2° and 18.6° demonstrating the amorphous nature of
HPβCyD. For HPβCyD/ibuprofen-IC (2:1) nanofibers retains the amorphous pattern of HPβCyD
with broad halos. On the contrary, XRD pattern of HPβCyD/ibuprofen-IC (1:1) nanofibers has
shown the typical diffraction peaks of ibuprofen suggesting the presence of some ibuprofen
crystals in the nanofibers. This correlates with the appearance of HPβCyD/ibuprofen-IC (1:1)
solution where the solution was turbid due to presence of some uncomplexed and undissolved
ibuprofen crystals (Figure 2b). In case of HPβCyD/ibuprofen-IC (2:1) nanofibers, the absence of
ibuprofen peaks suggests the total encapsulation of ibuprofen molecules inside the HPβCyD
cavities, since the inclusion complexation hinders the formation of ibuprofen crystals by
separating ibuprofen molecules from each other. The solution of HPβCyD/ibuprofen-IC (2:1)
was also clear and homogeneous without any visible ibuprofen crystals (Figure 2c), so, the
electrospun HPβCyD/ibuprofen-IC (2:1) nanofibers have totally amorphous ibuprofen. For
HPβCyD/ibuprofen-IC (1:1) nanofibers, the XRD peaks for crystalline ibuprofen was present but
the peak intensity was reduced suggesting that the amount of crystalline ibuprofen was minimal.
The SEM images (Figure 2b) didn’t show any presence of ibuprofen crystals for
HPβCyD/ibuprofen-IC (1:1) nanofibers further suggest that the amount of ibuprofen crystals was
not in high quantity. The HPβCyD/ibuprofen (1:1) physical mixture is another evidence for the
less amount of uncomplexed ibuprofen existing in HPβCyD/ibuprofen-IC (1:1)-IC nanofibers
(Figure 5a). HPβCyD/ibuprofen (1:1) physical mixture contains the same amount of ibuprofen
with HPβCyD/ibuprofen-IC (1:1) nanofibers, however the intensity of the XRD peaks of
ibuprofen is significantly higher in case of physical mixture compared to HPβCyD/ibuprofen-IC
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(1:1) nanofibers. It is because there is no complex formation in case of HPβCyD/ibuprofen (1:1)
physical mixture and it contains total ibuprofen crystals (Figure 5a) whereas only some
uncomplexed ibuprofen was present in crystalline form in HPβCyD/ibuprofen-IC (1:1)
nanofibers resulting less peak intensity in XRD. In short, complete amorphization of ibuprofen
was achieved for HPβCyD/ibuprofen-IC (2:1) nanofibers whereas some ibuprofen crystals were
present in HPβCyD/ibuprofen-IC (1:1) nanofibers due to the presence of some uncomplexed
ibuprofen.
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Figure 5. (a) XRD patterns and (b) DSC thermograms of pure ibuprofen powder, pure HPβCyD
nanofibers, HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibers and HPβCyD/ibuprofen (1:1)
physical mixture.
The solid-state interaction between CyD and guest molecules can lead to changes in the
thermal behavior of complex components.58,59 The disappearance, shift, reduction and/or
broadening of the endothermic melting peaks of guest and/or CyD molecules are evidence for the
complete or partial complexation.58,59 DSC thermograms of pure ibuprofen powder, pure
HPβCyD nanofibers, HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibers and HPβCyD/ibuprofen
(1:1) physical mixture are depicted in Figure 5b. While the DSC thermogram of pure HPβCyD
nanofibers indicates the characteristic broad peak of dehydration, ibuprofen thermogram displays
a sharp melting peak at 77 °C confirming its crystalline nature. For HPβCyD/ibuprofen-IC (2:1)
nanofibers, the absence of ibuprofen melting peak demonstrated the complete inclusion complex
formation between HPβCyD and ibuprofen.12,28,60 In case of HPβCyD/ibuprofen-IC (1:1)
nanofibers, the endothermal peak intensity/area of ibuprofen was reduced compared to
HPβCyD/ibuprofen (1:1) physical mixture. The melting point peak area of ibuprofen is measured
as 5.1 J/g for HPβCyD/ibuprofen-IC (1:1) nanofibers whereas the physical mixture of
HPβCyD/ibuprofen-IC (1:1) has the melting point peak area of 13.5 J/g. Considering the
presence of same amount of ibuprofen in HPβCyD/ibuprofen-IC (1:1) nanofibers and physical
mixture of HPβCyD/ibuprofen-IC (1:1), the ~2/3 reduction of peak intensity/area of ibuprofen in
HPβCyD/ibuprofen-IC (1:1) nanofibers suggested that ibuprofen was mostly in amorphous state
and being complexed with HPβCyD, yet, some uncomplexed and crystalline ibuprofen was
present in HPβCyD/ibuprofen-IC (1:1) nanofibers. The DSC data correlates with XRD analysis,
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HPβCyD/ibuprofen-IC (1:1) nanofibers contain partially amorphous ibuprofen whereas the total
amorphization of ibuprofen was achieved for HPβCyD/ibuprofen-IC (2:1) nanofibers.
The thermo-analytic analyses of pure ibuprofen, pure HPβCyD nanofibers and
HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibers were performed by using TGA (Figure 6). The
ibuprofen powder exhibits one-step mass loss from ~150 °C up to 222 °C. For pure HPβCyD
nanofibers, there are two main weight losses from 25 °C to 400 °C which correspond to water
loss (up to 100 °C) and the main degradation of HPβCyD (max. temp 358 °C). On the other
hand, three steps mass losses were observed in both HPβCyD/ibuprofen-IC (1:1) and
HPβCyD/ibuprofen-IC (2:1) nanofibers thermograms; i) water loss, ii) main degradation of
ibuprofen and iii) main degradation of HPβCyD. As seen from the derivative curves, the main
degradation of ibuprofen shifts to lower temperature of 192 °C and 205 °C for
HPβCyD/ibuprofen-IC (1:1) and HPβCyD/ibuprofen-IC (2:1) nanofibers, respectively. The
slightly lower degradation temperature of ibuprofen in HPβCyD/ibuprofen-IC nanofibers
supports the amorphous distribution of ibuprofen molecules in these samples unlike its
crystalline powder form.62 Since HPβCyD/ibuprofen-IC (1:1) nanofibers contain higher amount
of ibuprofen (12.9% (w/w), with respect to total sample amount) than HPβCyD/ibuprofen-IC
(2:1) nanofibers (6.9% (w/w), with respect to total sample amount), the degradation of ibuprofen
probably shifts to lower temperature in case of HPβCyD/ibuprofen-IC (1:1) nanofibers (192 °C)
compared to HPβCyD/ibuprofen-IC (2:1) nanofibers (205 °C). It is also possible to calculate the
components ratios in the samples by using TGA technique. When the weight loss up to 270 °C is
considered from TGA thermograms of HPβCyD/ibuprofen-IC nanofibers, the amount of
ibuprofen was determined to be ~8.8% (w/w, with respect to total sample amount) and ~5.4%
(w/w, with respect to total sample amount) for HPβCyD/ibuprofen-IC (1:1) nanofibers and
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HPβCyD/ibuprofen-IC (2:1) nanofibers, respectively. These findings are not totally correlated
with the 1H-NMR results and initial ratios of 12.9% (w/w) and 6.9% (w/w) ibuprofen were used
for the preparation of HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1)
nanofibers, respectively. However, it is actually obvious from the TGA derivate curves that there
was an additional degradation step between 270 °C and 320 °C for both HPβCyD/ibuprofen-IC
nanofibers, which is partially buried under the main degradation of HPβCyD (Figure 6b). The
higher degradation temperature of ibuprofen possibly originated from stronger interactions
between ibuprofen and HPβCyD compared to ibuprofen which has low temperature degradation
observed at ~200 °C. Actually, the increase in thermal stability of guest molecules is very
common for CyD inclusion complex systems and such improved thermal stability for the guest
molecules is considered as an evidence of inclusion complexation.59 Here, the TGA data suggest
that ibuprofen has different strengths of interactions with HPβCyD in HPβCyD/ibuprofen-IC
nanofibers. The exact amount of ibuprofen in HPβCyD/ibuprofen-IC nanofibers could not be
accurately calculated from the TGA thermograms due to overlapped degradation steps.
Nonetheless, the TGA analysis revealed the inclusion complexation state between ibuprofen and
HPβCyD in HPβCyD/ibuprofen-IC nanofibers by means of altered degradation temperature of
ibuprofen.
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Figure 6. (a) TGA thermograms and (b) derivates of pure ibuprofen powder, pure HPβCyD
nanofibers, HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-IC (2:1) nanofibers.
3.3. Pharmacotechnical Properties of HPβCyD/Ibuprofen-IC Nanofibers. Phase
solubility analyses are widely performed for CyD and hydrophobic drug complexes to get
information about the solubilizing effect of CyD on drug molecules and to calculate the stability
constants of inclusion complexes.63,64 Here, the dynamic equilibrium was reached up to 24 h and
UV-Vis spectroscopy technique was used to examine the filtered aliquot of HPβCyD/ibuprofen
solutions having different HPβCyD concentrations. The phase solubility diagram (Figure 7a)
indicates the solubility manner of ibuprofen against increasing HPβCyD concentrations from 0 to
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10 mM. It is obvious from the findings that the ibuprofen solubility was increased ~7 times in the
10 mM concentrated solution of HPβCyD due to the complex formation. As described by
Higuchi and Connors method51, phase solubility diagrams can be obtained with different profiles
depending on the types of CyD and guest molecules.51 A-type phase solubility diagram has
subtypes of AL, AN and AP which stands for linear increases in guest solubility as a function of
CyD concentration, positively deviation of isotherms and negatively deviation of isotherms,
respectively.51,63 In our case, the phase solubility diagram exhibit the AN-type pattern suggesting
the highest HPβCyD concentration of 10 mM is the approximate limits and less effective for the
solubilization of ibuprofen. On the other hand, the straight-line portion of the diagram enables
the calculation of the stability constant (Ks) from its slope. The Ks value essentially represents
the binding strength between guest molecules and CyD cavity and it was calculated as 810 M-1
for the HPβCyD/ibuprofen system.
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Figure 7. (a) Phase solubility diagram of HPβCyD/ibuprofen-IC system. (b) UV-Vis spectra of
aqueous solutions of ibuprofen, HPβCyD/ibuprofen-IC (1:1) nanofibers and HPβCyD/ibuprofen-
IC (2:1) nanofibers.
The solubility enhancement of ibuprofen was also proved by comparing the dissolution of
pure ibuprofen and HPβCyD/ibuprofen-IC nanofibers in water. For this purpose, ibuprofen and
HPβCyD/ibuprofen-IC nanofibers including the same amount of ibuprofen were dissolved in
water in a definite period of time (24 h), and then UV–Vis spectroscopy measurements were
performed for the resulting aqueous solutions. Prior the measurements, the solutions were
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filtered to eliminate the undissolved parts of ibuprofen if present. Figure 7b displays the UV-Vis
spectra of aqueous solutions of ibuprofen and HPβCyD/ibuprofen-IC nanofibers in which the
characteristic absorptions of ibuprofen were clearly recorded. It is obvious from the UV-Vis
spectra that the absorption intensity of the solutions in which HPβCyD/ibuprofen-IC nanofibers
were dissolved is much higher than the solution in which pure ibuprofen powder was prepared
having the same amount (2 mM). This higher intensity occurrence in UV–Vis-spectra for
ibuprofen clearly indicated that ibuprofen became water soluble due to the inclusion
complexation between HPβCyD and ibuprofen in HPβCyD/ibuprofen-IC nanofibers. When
dissolved, the HPβCyD/ibuprofen-IC (1:1) nanofibers and the HPβCyD/ibuprofen-IC (2:1)
nanofibers depict almost the same intensity at UV-Vis spectra, because HPβCyD/ibuprofen-IC
(1:1) (~17 mg) and HPβCyD/ibuprofen-IC (2:1) (~30 mg) nanofibers were weighted so as to
include the same amount of ibuprofen for the measurement. This result also suggests that
ibuprofen was completely dissolved in water for both samples of HPβCyD/ibuprofen-IC
nanofibers even though HPβCyD/ibuprofen-IC (1:1) nanofibers had some uncomplexed
crystalline ibuprofen. This is possibly because the experiment was performed in more diluted
aqueous environment compared to electrospinning solution and HPβCyD/ibuprofen-IC (1:1)
nanofibers were dissolved and stirred for 24 h prior the UV-Vis measurement which is quite
enough time for uncomplexed ibuprofen molecules to form inclusion complexes with free
HPβCyD molecules.
The rapid dissolution of webs of HPβCyD/ibuprofen-IC nanofibers was examined by
adding 3 mL of water to the vials which contain equivalent amount of ibuprofen (~5mg) (Figure
8a). Same amount of pure ibuprofen powder was also tested for comparison. The
HPβCyD/ibuprofen-IC nanofibrous webs collapsed in the first seconds by the addition of water
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and clear solutions were obtained in less than few seconds for HPβCyD/ibuprofen-IC nanofibers
(Figure 8a, Video S1). To have the same amount of ibuprofen in HPβCyD/ibuprofen-IC
nanofibrous webs, we used almost double amount of HPβCyD/ibuprofen-IC (2:1) nanofibrous
web (~72 mg) compared to HPβCyD/ibuprofen-IC (1:1) nanofibrous web (~38 mg). Even so, the
fast dissolving character was observed for both HPβCyD/ibuprofen-IC nanofibrous webs
resulting complete dissolution of the webs and clear solutions without any indication of
undissolved ibuprofen. In contrast, the pure ibuprofen powder remained at the bottom of the vial
over this period time without dissolution showing that it is a poorly water-soluble drug (Figure
8a).
The disintegration of HPβCyD/ibuprofen-IC nanofibrous webs was further investigated
using wet filter paper to simulate the moist environment of oral cavity.52 As it is observed in
Figure 8b, and Video S2, the HPβCyD/ibuprofen-IC nanofibrous webs were rapidly adsorbed by
artificial saliva and dissolved instantly. The high water solubility of HPβCyD31 is a considerable
factor for the high dissolution and disintegration rate of the HPβCyD/ibuprofen-IC nanofibrous
webs. In addition, the highly porous structure and high surface area of nanofibers provide
remarkable penetration path and interaction side for aqueous system through the nanofibrous
webs, which also ensure the rapid disintegration and dissolution of the nanofibers.11 To conclude,
saliva can be easily penetrate through the pores of the HPβCyD/ibuprofen-IC nanofibrous webs
when it is placed in the mouth and the fast disintegration of the HPβCyD/ibuprofen-IC
nanofibrous webs can guarantee the instant release of ibuprofen.
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Figure 8. (a) The dissolution behavior of pure ibuprofen powder, HPβCyD/ibuprofen-IC (1:1)
and HPβCyD/ibuprofen-IC (2:1) nanofibrous webs in distilled water. (b) The disintegration
behavior of HPβCyD/ibuprofen-IC (1:1) and HPβCyD/ibuprofen-IC (2:1) nanofibrous webs at
the artificial saliva environment. The pictures were captured from the videos which were given
as Video S1 and Video S2.
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4. CONCLUSION
Cyclodextrins (CyDs) are very effective for water solubility enhancement for poorly
water-soluble drugs by forming inclusion complexation. The electrospinning of nanofibers from
CyD/drug inclusion complexes is very promising approach to produce fast dissolving
nanofibrous webs for oral drug delivery systems. Here, we have chosen hydroxypropyl-beta-
cyclodextrin (HPβCyD), a highly water soluble CyD derivative which is being used for drug
formulations, in order to function both as a nanofiber matrix and complexation agent in order to
enhance water solubility and fast dissolution of poorly water-soluble ibuprofen. The
electrospinning process was successfully performed to produce bead-free and uniform
HPβCyD/ibuprofen-IC nanofibers having ~200 nm fiber diameter. The percent loading of drug
could be adjusted since HPβCyD/ibuprofen-IC solutions having different molar ratios (e.g.; 1:1
and 2:1, HPβCyD:ibuprofen) can be electrospun into nanofibers in the form of self-standing and
flexible nanofibrous webs. The HPβCyD/ibuprofen-IC nanofibrous webs have shown very fast
dissolving character when contacted with water or when wetted with artificial saliva suggesting
that such electrospun HPβCyD/ibuprofen-IC nanofibrous webs have shown potential as fast
dissolving oral drug delivery system. It is also noteworthy to mention that the electrospinning of
HPβCyD/ibuprofen-IC nanofibers was performed in water since ibuprofen become water soluble
by HPβCyD. The use of only water provides a great advantage in terms of industrial processing
aspect for the development of such fast dissolving oral drug delivery systems based on CyD/drug
inclusion complex nanofibers. In brief, CyDs can form inclusion complexation with variety of
drug molecules; so, this proof-of-concept study with ibuprofen can be extended with other drug
molecules in order to develop fast dissolving oral drug delivery systems based on electrospun
nanofibrous webs of CyD/drug inclusion complex nanofibers.
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ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website at DOI:
The comparative dissolution (Video S1) and disintegration (Video S2) profile of Ibuprofen
powder and HPβCyD/ibuprofen-IC nanofibers.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: [email protected] (A.C.)
*E-mail: [email protected] (T.U.)
ORCID IDTamer Uyar: 0000-0002-3989-4481
Present Addresses
Department of Fiber Science & Apparel Design, College of Human Ecology, Cornell University,
Ithaca, NY, 14853, USA
Author Contribution: T. U. and A.C. designed the study. A.C. performed the experimental
studies. A.C. and T. U. wrote the manuscript and have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work made use of the scanning electron microscope (SEM) and X-Ray diffractometer
(XRD) of the Cornell Center for Materials Research Shared Facilities which are supported
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through the NSF MRSEC program (DMR-1719875). Prof. Uyar acknowledges the startup
funding from the College of Human Ecology at Cornell University. The partial funding for this
research was also graciously provided by Nixon Family (Lea and John Nixon) thru College of
Human Ecology at Cornell University.
For Table of Contents Only
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