Journal of Drug Delivery Science and Technology 66 (2021) 102878

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Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst

Tableted hydrophilic electrospun nanofibers to promote meloxicam

dissolution rate
Silvia Pisani a, Valeria Friuli b, *, Bice Conti b, Giovanna Bruni c, Lauretta Maggi b
a
Department of Otolaryngology, IRCCS Policlinico S. Matteo, 27100, Pavia, Italy
b
Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100, Pavia, Italy
c
Department of Chemistry, Physical-Chemistry Section, University of Pavia, Via Taramelli 16, 27100, Pavia, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: This study investigated the ability of hydrophilic electrospun nanofibers to enhance the dissolution rate of poorly
Hydrophilic nanofibers soluble drug Meloxicam (MLX). The drug was loaded into polyvinylpyrrolidone (PVP), polyvinyl capro­
Tableted nanofibers lactam–polyvinyl acetate–polyethylene glycol (Soluplus®), sodium lauryl sulfate (SLS) nanofibers using elec­
Polyvinylpyrrolidone
trospinning as fibers fabrication technique. The drug-loaded nanofibers were characterized for their diameter,
Meloxicam
Dissolution rate
inter-fibers porosity and drug dissolution profiles, carried out in four different aqueous buffers. Nanofibers
Electrospinning loaded with MLX were grinded and used to prepare a solid unit dosage form (Tablets: 7 mm × 4 mm) to facilitate
Nanofibers their administration. Fibers nanostructure was characterized through SEM analysis showing a mean diameter in a
Tableted fibers nanometer size range. Moreover, SEM confirmed the maintenance of fibrous structure within tablets cross
Hydrophilic polymers section.
Tablets Dissolutions rate of MLX-loaded nanofibers is improved, compared to free drug, suggesting that nanofibers
could be used as suitable carrier to enhance MLX dissolution rate. Moreover, the tablet formulation proposed
showed faster release rate in comparison with commercial oral forms (Mobic®) particularly in the dissolution
media characterized by lower pHs.

1. Introduction Electrospinning has emerged as an innovative, reproducible and in­

One of the most common limiting steps in drugs absorption is their
poor water solubility that is correlated to low bioavailability. Many
strategies were developed to enhance the dissolution rate of poorly
water-soluble compounds for oral administration, e.g. addition of sur­
factant and/or wetting agents, dispersion of amorphous solid, and
vehiculation in hydrophilic polymers [1].
Currently, tablets are the most predominant and frequently used
medication form [2]. In Tablets, as immediate release dosage form, one
or more active substances are homogeneously mixed with excipients
improving drug dissolution and bioavailability. The most common hy­
drophilic excipients used are: hydroxypropyl methylcellulose (HPMC),
lactose, citric acid, polyvinylpyrrolidone (PVP), polyethylene glycol, etc
[3].
Innovative techniques for tablet manufacturing were proposed to
develop alternative solid dosage forms able to achieve dose flexibility,
personalized therapy and improved patient compliance [4].
dustrial scalable manufacturing technique, able to produce fibers
ranging from micrometer to nanometer by applying an external electric
field on a polymeric solution. Fibers obtained exhibit high surface area
to volume ratio, high porosity range, reproducible and controllable
diameter and good drug loading capacity [5,6]. These characteristics
can be usefully exploited in order to improve the dissolution rate of
poorly water soluble drugs [7]. Moreover, to facilitate oral fibers
administration, the possibility to compress grinded fibers to obtain
tablets was evaluated [8,9]. Due to the versatility demonstrated by
electrospun nanofibers their future use in pharmaceutical production is
promising; polymeric fibers can be considered an intermediate in the
production of oral dosage forms (tablets or filling capsules) or a finished
pharmaceutical dosage form such as fast dissolving web [10,11].
In literature some interesting examples reported the use of polymeric
electrospun nanofibers as carrier for poorly soluble drugs (such as
ketoprofen, ibuprofen, paracetamol, caffeine, acetyl salicylic acid, car­
vedilol, ondansetron, nebivolol and meloxicam). Polymers such as Poly

* Corresponding author.
E-mail addresses: s.pisani@smatteo.pv.it (S. Pisani), valeria.friuli@unipv.it (V. Friuli), bice.conti@unipv.it (B. Conti), giovanna.bruni@unipv.it (G. Bruni),
lauretta.maggi@unipv.it (L. Maggi).

https://doi.org/10.1016/j.jddst.2021.102878
Received 15 July 2021; Received in revised form 15 September 2021; Accepted 23 September 2021
Available online 21 October 2021
1773-2247/© 2021 Elsevier B.V. All rights reserved.
S. Pisani et al.
vynil pyrrolidone (PVP), Poly vynil alcohol (PVA), Dextran blends and
Eudragit polymers were investigated as suitable carriers for nanofibers
manufacturing and drug vehiculation demonstrating high drug payload
and fast dissolution performances [12,13].
Casian et al., developed through electrospinning technique, a
meloxicam amorphous orodispersible web made from PVP30 and
Eudragit E [14]. Varma et al., developed PVP30:hydrox­
ypropyl-β-cyclodextrin nanofibers loaded with Meloxicam; their opti­
mized nanofibers, formulated into capsules, showed a 7 fold dissolution
rate increase compared to free drug [15]. Maggi et al., prepared Fir­
ocoxib loaded PVP30 electrospun matrices supplemented with surfac­
tants and evaluated the effect of electrospun matrix composition on
Firocoxib dissolution rate. The authors concluded that a complete and
faster dissolution rate of Firocoxib from the electrospun fibers was
promoted with respect to the commercial reference product [16].
In this original scientific work, Meloxicam (MLX) was selected as
drug model to be incorporated inside hydrophilic nanofibers. MLX,
classified as a Biopharmaceutical Classification System (BCS) class II
drug, is practically insoluble in water (4.4 10− 3 mg/ml), it has low
wettability and poor dissolution properties in physiologic fluids that
compromise its bioavailability [17,18]. MLX pharmacological use in­
cludes anti-inflammatory and analgesic activity. Moreover, in clinical
studies, meloxicam has shown reliable efficacy against rheumatoid
arthritis, osteoarthritis, lumbago (low back pain), scapulohumeral per­
iarthritis, and neck-shoulder-arm syndrome with low gastrointestinal
toxicity [19].
The aim was to optimize a formulation able to give MLX loaded fibers
through the electrospinning set-up. PVP10 was combined with surfac­
tants Polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol
(Soluplus®) and Sodium lauryl sulfate (SLS) to obtain nanofibers able to
further increase MLX dissolution rate. These surfactants were selected
because they have already been proved to be useful in increasing
wettability and bioavailability of poorly soluble drugs [20,21]. Hydro­
philic electrospun nanofibers would enhance MLX wettability and
dissolution rate in water and in different aqueous media simulating in
vitro physiologic conditions. Moreover, the nanofibers higher surface
area to volume ratio allows for better contact with aqueous buffers, thus
promoting MLX solubility.
Optimized MLX polymeric electrospun fibers, were ground and
compressed to obtain tablets. Moreover, a pharmaceutical formulation
mixing MLX nanofibers and different excipients, was designed and
tablets were prepared. Obtained products were characterized for their
physico-chemical properties, and MLX dissolution performances. MLX
pure and Mobic®, commercial product, were used as references.
The novelty proposed in this manuscript concerns the alternative use
of drug-loaded electrospun nanofibers as raw material for tablets
manufacturing. Drug-loaded nanofibers, due to their peculiar proper­
ties, demonstrated improved release behavior compared to free drug
(especially for low soluble ones) [19]. The possibility of ground and
compress nanofibers to obtain tablets, maintaining the suitable drug
dissolution profile represents an important and advantageous alterna­
tive approach in the production of pharmaceutical oral forms.
2. Materials
Meloxicam (MLX) was kindly donated by AMSA S.p.A. (Milano,
Italy). Polyvinylpyrrolidone average mol wt. 10.000 (PVP10) was sup­
plied by the SIGMA-ALDRICH Co. (Missouri, USA), polyvinyl
caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer,
Soluplus® (SOL) was obtained through BASF (Ludwigshafen, Germany)
and Sodium lauryl sulfate (SLS) was supplied by Carlo Erba (Milano,
Italy).
Methylene Chloride (MC) and Dimethyl-formamide (DMF) were
supplied by Carlo Erba (Milano, Italy) and they were used to solubilize
the drug, the polymeric materials and the surfactant.
Microcrystalline cellulose NF, Avicel® (FMC, Philadelphia, PA),
2
Journal of Drug Delivery Science and Technology 66 (2021) 102878
cross linked polyvinylpyrrolidone, Polyplasdone® XL (GAF, New York,
NY), Talc (Carlo Erba, Milan, Italy), silicon dioxide, Syloid® 72FP
(Grace GmbH, Worms, Germany) and magnesium stearate (Carlo Erba,
Milan, Italy) were used to prepare TabFS9.
Mobic® 7,5 mg tablets (Boehringer Pharma GmbH, Ingelheim am
Rhein, Germany), was used as reference.
All the dissolution media were prepared according to the USP re­
agents section (Pharmacopeia, 2020b) using potassium dihydrogen
phosphate (AppliCHEM PanReac GmbH, Germany), sodium hydroxide
(Carlo Erba Reagents, Italy) and hydrochloric acid (Sigma Aldrich,
USA).
Unless specified, all other solvents and reagents were of analytical
grade.
3. Methods
3.1. Polymeric electrospun nanofibers preparation
Polyvinylpyrrolidone (PVP10) and Soluplus® (SOL) were selected to
prepare polymeric electrospun nanofibers. The polymers were solubi­
lized in an organic solvents blend consisting of Methylene Chloride (MC)
and Dimethyl-formamide (DMF) in 70:30 ratio. Organic solvents blend
was optimized to take advantages from low boiling point of MC (39.6 ◦ C)
and dielectric constant of DMF (ε = 36.7) suitable for electrospinning
process (Hecht et al., 2003).
PVP10 concentration was fixed at 20%w/v while SOL concentration
was progressively increased (20% w/v, 30%w/v and 40% w/v) to
evaluate the SOL influences in fibers formation (diameter and
morphology).
Subsequently Meloxicam (MLX) was solubilized 1.5% w/v in DMF
and added to the polymeric solutions. The composition that showed the
best dissolutions rate was supplemented with a second surfactant, So­
dium lauryl sulfate (SLS) at 1%w/v. MLX and SLS additions were eval­
uated in terms of nanofiber morphology and MLX dissolution rate.
Subsequently MLX concentration was increased up to 3% w/v to eval­
uate the effect of drug concentration on dissolution rate.
Electrospinning apparatus NANON-01 (MECC Instruments, Ltd, Ogo-
shi, Fukuoka, Japan) equipped with a dehumidifier system (196-1
Fukudo Ogori-Shi, Japan) was used to electrospun the polymeric fibers.
Each solution prepared was loaded in 5 mL Luer lock plastic syringe
(Luer lock syringe, Germany) and pumped through the syringe needle
fixed at the metal spinneret support. Following the application of an
electric field induced by high voltage between the syringe needle (pri­
mary electrode) and the collector (counter electrode) dry fibers were
collected on a metallic plate. Environment parameters were maintained
constant at 23 ± 2 ◦ C and relative humidity percentage (RH%) 30% ± 5.
The needle-collector distance was fixed at 15 cm using a 18 Gauge (G)
needle and a plate collector coated with an aluminum foil to facilitate
the nanofibers recovery.
Working parameters such as voltage (kV) and flow rate (mL/h) were
optimized to obtain homogeneous and defect-free fibers in a nanometer
size range. After production, the fibers were stored under vacuum and
then used for following characterization.
3.2. Tablets preparation
MLX electrospun fibers that showed in vitro better dissolution profiles
were selected for following tablets preparation.
The nanofibers were left overnight under laminar hood and then
stored under vacuum to promote evaporation of residual solvents.
Recovered MLX loaded nanofibers were grinded in a mortar and then
sieved through a 270 mesh grid (53 μm) to obtain a more uniform size
distribution. The resulting product was weighed to have 7.5 mg of
meloxicam and tableted using a single -punch machine (Korsch EK0;
Korsch AG, Berlin, Germany) equipped with 7 mm in diameter flat
punches at 35 kN. This sample was coded “Tab” plus the identification
S. Pisani et al. Journal of Drug Delivery Science and Technology 66 (2021) 102878

name of the starting fibers from which is derived.
Moreover, a complete formulation was designed, containing excipi­
ents to improve both the tableting process and the dissolution rate of the
active (Table 1). Microcrystalline cellulose NF (Avicel®), Poly­
plasdone® XL, Talc, Syloid® 72FP and magnesium stearate were mixed
with MLX-nanofibers in a Turbula apparatus (Turbula T2A; Bachofen,
Basel, Switzerland). The tablets were prepared using the same single
-punch machine reported above equipped with the same punches. The
resulting tablets were called “TabF” plus the identification name of the
fibers sample from which they derived.
3.3. Morphological characterization: Scanning Electron Microscopy
(SEM)
A Zeiss EVO MA10 (Carl Zeiss, Oberkochen, Germany) was used to
analyze the morphology of the nanofibers (10 kX magnification) and of
the tablets obtained from MLX nanofibers (5 kX magnification). The
samples were gold-sputter coated under argon to render them electri­
cally conductive prior the microscopy.
The average diameter and standard deviation (±SD) of the fibers was
determined by the ImageJ software, an image processing program
designed for scientific multidimensional images and based on plugin
series Diameter J (Schneider et al., 2012). A number of 50 fibers from
the microphotographs of each sample were considered for the analysis.
Mean pores area and porosity % of nanofibers network and Tab were
analyzed by the same program too.
3.4. Differential scanning calorimetry (DSC)
Differential scanning calorimetry (DSC) analysis was performed on
powder raw materials (PVP10, SOL, SLS and MLX), on polymeric nano­
fibers and MLX loaded electrospun samples. DSC Q2000 apparatus
interfaced with a TA 5000 data station (TA Instruments, New Castle, DE,
USA) was used. The instrument was calibrated using ultrapure indium
(99.999%; melting point = 156.6 ◦ C; melting enthalpy = 28.54 J g− 1) as
standard. The samples (about 3.5–4 mg) were scanned heating at 5 K
min− 1 under nitrogen flow (45 ml min− 1) in open standard aluminum
pans.
3.5. Technological characterization: contact angle and hardness testing
Contact angle (θ) was used to evaluate the attitude of a solid to be
wetted by a liquid. The contact angles of: pure MLX, fibers loaded with
MLX (S9), tablets obtained after fibers compression (TabS9) and tablets
obtained from the formulation proposed (TabFS9) were determined.
Contact angle meter DMe-211Plus was used for contact angle
determination using as wetting liquid, the same media of the dissolution
test (deionized water, HCl 0.1 N pH 1.0, buffer pH 4.5 and buffer pH
7.5).
A 9 μl drop was extruded from the needle and put into contact with
solid surface. Contact angle was measured at t = 0 and after 60sec.
The tablets obtained from fibers compression (Tab) and from the
formulation F (TabF) were characterized in terms of diameter, thickness
and weight (METTLER TOLEDO AE260 DeltaRange®, Milan, Italy). The
average values ± standard deviation were reported. Moreover, the
crushing strength of tablets was measured on 6 tablets with a suitable
apparatus equipped with a high sensitive load washer (Kistler, Winter­
thur, CH).
Mobic® was in the form of coated tablets, for this reason the contact
angle determination and the hardness test were not performed because
the results will not be comparable with those obtained from uncoated
TabS and TabFS.
3.6. In vitro dissolution tests
The dissolution test of MLX from electrospun nanofibers was per­
formed using paddle method (Erweka DT-D6, Dusseldorf, Germany) at
37.0 ± 0.5 ◦ C, 75 rpm, in 900 mL of deionized water (pH 6.7) and in
three different aqueous buffers, to mimic the physiologic conditions of
the gastrointestinal tract: pH 1.0 to simulate fasting stomach conditions,
pH 4.5 to simulate the gastric fed state, while dissolution in deionized
water was performed to simulate the usual administration with a glass of
water. Finally, pH 7.5 buffer is the dissolution medium prescribed in the
official monograph of MLX tablets [18]. Three replicates for each sample
were performed and data were reported with ±SD.
The amount of drug dissolved was determined by UV detection on
filtered portion of the dissolution fluid at 362 nm with a spectropho­
tometer (Lambda 25; PerkinElmer) and data were processed by an in­
tegrated software (Winlab V6 software, PerkinElmer, Monza, Italy).
In vitro dissolution test was performed on the nanofiber samples, and
the results were used as discriminating criteria to select the most suit­
able composition to prepare the tablets (as reported above in Par. 3.2).
The tablets obtained from the selected nanofiber sample (Tab) and the
tablets obtained from the formulation F (TabF) were tested in the same
conditions. The dissolution profile of MLX free drug (7.5 mg) and
Mobic® 7,5 mg were used as references.
4. Results
4.1. Polymeric electrospun nanofibers preparation
Placebo and MLX loaded electrospun nanofibers were obtained using
PVP10 and SOL as structural polymeric components. Table 2 summa­
rized the starting solutions compositions (S1–S9) and the electro­
spinning process parameters optimized for nanofibers manufacturing.
Nanofiber size analysis results, performed by ImageJ software, are also
reported in Table 2. The results showed that the composition of poly­
meric solutions significantly affected nanofiber diameter.
Starting with PVP10 and SOL both at concentration of 20% w/v (S1)
and increasing SOL amount at 30% (S2) and 40% (S3) fibers showed a
Table 2
Morphometric characterization of electrospun fibers and the corresponding
composition of electrospun polymer solutions and electrospinning process
parameters.
Composition of electrospun polymer Electrospinning Fibers
solutions process parameters diameter
(nm ± SD)
Fibers PVP SOL SLS MLX Voltage Flow
(%w/ (% (% (%w/ (kV) Rate
v) w/v) w/v) v) (mL/
h)

S1 20.0 20.0 – – 26.5 0.4 313 ± 0.15

Table 1 S2 20.0 30.0 – – 27.5 0.2 587 ± 0.28
Single unit composition of the formulation F containing S9 fibers. S3 20.0 40.0 – – 30 0.4 1330 ±
0.16
S9 (corresponding 7.5 mg of Meloxicam) 110 mg
S4 20.0 20.0 – 1.5 26.5 0.3 330 ± 0.14
Microcrystalline cellulose NF, Avicel® (FMC, Philadelphia, PA) 90 mg
S5 20.0 30.0 – 1.5 27.5 0.2 594 ± 0.15
Polyplasdone® XL (GAF, New York, NY) 30 mg
S6 20.0 40.0 – 1.5 30 0.4 1375 ±
Talc (Carlo Erba, Milan, Italy) 1 mg
0.21
Syloid® 72FP (Grace GmbH, Worms, Germany) 0.5 mg
S7 20.0 20.0 1.0 1.5 29 0.3 440 ± 0.10
Magnesium stearate (Carlo Erba, Milan, Italy) 1 mg
S8 20.0 20.0 – 3.0 29 0.3 396 ± 0.12
Total weight 232.5 mg S9 20.0 20.0 1.0 3.0 30 0.3 529 ± 0.14

3
S. Pisani et al.
significant progressive increase in size with values respectively of 313 ±
0.05 nm (S1), 587 ± 0.08 (S2) and 1330 ± 0.16 (S3).
Following addition of 1.5%w/v of MLX did not significantly affect
fibers size for all polymeric solutions tested, showing values of 330 ±
0.04 nm (S4), 594 ± 0.15 (S5) and 1375 ± 0.21 nm.
Fibers remained in a nanometer size range for samples S1, S2, S4, S5,
instead a micrometer size range was achieved increasing SOL up to 40%
w/v (S3 and S6).
Considering the values of fibers diameters reported in Table 2 ob­
tained and referring to SEM images (Fig. 1) and MLX dissolution release
profile of S4, S5 and S6 batches (Fig. 5), fibers obtained from solution S4
(PVP10 20%w/v, SOL 20%w/v and MLX 1.5% w/v) were selected as best
composition and were used for further studies.
SLS 1%w/v (sample S7), added with the aim of improve MLX
dissolution rate and permit higher MLX payloads into the electrospun
matrices, caused an increase in fiber size up to 440 ± 0.10 nm that
further increased at 529 ± 0.14 nm when 3%w/v MLX was added
keeping constant polymer and surfactant composition (sample S9).
Greater increase in fiber size was achieved after addition of SLS (S7
and S9), while increase of MLX at 3%w/v didn’t affect remarkably fiber
size. However, fibers diameter remained in a nanometer size range
suitable to exploit high surface area to volume ratio.
Spinning time was decided considering MLX concentrations in
polymeric solutions (1.5%w/v for S4 and S7 and 3%w/v for S8 and S9)
and flow-rate (0.3 ml/h) optimized to obtain defect-free polymeric
nanofibers.
The drug content (MLX) in the electrospun nanofibers was verified in
phosphate buffer pH = 7.5 because the drug is soluble at this pH [18]
using a calibration curve previously performed at 362 nm, 1 cm cell,
with a correlation coefficient of 0.9988.
4.2. Morphological characterization: Scanning Electron Microscopy
(SEM)
In Fig. 1 are reported SEM Images obtained for MLX loaded elec­
trospun nanofibers for samples S4 (Fig. 1a), S7 (Fig. 1b), S8 (Fig. 1c) and
Fig. 1. Scanning Electron Microscopy (SEM) of: a) S4 (PVP10 20%w/v + SOL 20% w/v + 1.5%w/v MLX); b) S7 (PVP10 20%w/v + SOL 20% w/v + SLS 1%w/v +
1.5%w/v MLX); c) S8 (PVP10 20%w/v + SOL 20% w/v + 3%w/v MLX); d) S9 (PVP10 20%w/v + SOL 20% w/v + SLS 1%w/v + 3%w/v MLX).
4
Journal of Drug Delivery Science and Technology 66 (2021) 102878
S9 (Fig. 1d). In Fig. 2 are reported surface (Fig. 2b) and cross section
(Fig. 2c) SEM images of MLX tablets (TabS9) obtained through
compression of MLX nanofibers (Fig. 2a).
All electrospun nanofibers showed random dispersion compatible
with the use of a metallic plate collector. Nanofibers exhibited smooth
surface and homogeneous dimensions in a nanometer size range as re­
ported in Table 2 (samples S4, S7, S8 and S9).
SEM images of surface and cross section of tablets obtained com­
pressing PVP10 20%w/v + SOL 20% w/v + SLS 1%w/v + 3%w/v MLX
(TabS9), showed that fibers are still present in the tablets. Weak melting
phenomena are visible on tablet surface (Fig. 2 b) probably due to heat
developed during nanofibers compression phase.
SEM images of placebo nanofibers and MLX loaded nanofibers ob­
tained with different ratio of SOL are reported in supplementary data
(Supplementary Data Fig. S1).
Nanofibers network and TabS9 were characterized for their porosity
using ImageJ software (Supplementary data Fig. S2). Using SEM images
were performed a black/white threshold conversions and values of mean
pores area were calculated by software.
S9 Nanofibers showed a normalized porosity % of 6.86 ± 1.7%
measured over a total area of 100 μm2. Tab obtained after fibers
compression, showed a lower porosity % respectively of 1.15 ± 1.7%
and 1.12 ± 1.7% for cross section and surface.
4.3. Differential scanning calorimetry (DSC)
MLX shows a melting peak at 257.6 ◦ C followed by another endo­
thermic peak due to decomposition. These thermal effects are absent in
the DSC curve of the nanofibers loaded with MLX which show a thermal
behavior similar to that of the unloaded nanofibers. This indicates that
the drug in the fibers is in amorphous phase (Fig. 3).
4.4. Technological characterization: contact angle and hardness testing
Pure MLX, nanofibers sample (S9) and tablets (TabS9 and TabFS9)
were characterized for their wettability. Contact angles values obtained
S. Pisani et al. Journal of Drug Delivery Science and Technology 66 (2021) 102878

Fig. 2. a) tablets obtained by S9 fibers (TabS9 = 20% w/v PVP10:20%SOL:1%w/v SLS:3% w/v MLX); b) surface of TabS9; c) cross section of TabS9.

Table 4
Weight average, diameter, thickness and crushing strength of TabFS9 and
TabS9.
Tablet Weight ± Diameter ± SD Thickness ± SD Strength of
SD (g) (mm) (mm) crushing ± SD (N)

TabS9 0.109 ± 7.02 ± 0.01 5.10 ± 0.08 31 ± 2

0.001
TabFS9 0.231 ± 8.92 ± 0.02 4.76 ± 0.09 35 ± 1
0.001

strength of crushing value. However, values of crushing are suitable for

tablet use.

4.5. In vitro dissolution tests

A remarkable increase of the drug dissolution rate was obtained by

Fig. 3. DSC curves of 20%w/v PVP10 + 20%w/v SOL +1% w/v SLS (a) and
20%w/v PVP10 + 20%w/v SOL + 1%w/v SLS + 3%w/v MLX (b) and melox­
icam (MLX) (c).
using aqueous dissolution buffers are reported in Table 3.
Values of contact angle were reported at t0 and 60min after drop
contact (t60).
Values of contact angles θ < 90◦ denote solid high wettability instead
θ > 90◦ indicate solid low wettability. Pure MLX powder showed in all
tested aqueous buffers very low wettability, compatible with its classi­
fication in BCS class II.
However, MLX loaded in electrospun fibers, in all conditions
analyzed, showed values of θ lower than 90◦ . S9 fibers showed lower
values of contact angle compared to TabS9 with all aqueous buffer tested
probably due to the higher inter-fibers porosity and lower sample
thickness (0.092 ± 0.013 mm). Increasing drop contact time with solid
surface, values of contact angles measured for S9 and TabS9 decreased.
In all tested tables, lower values of contact angle compared to TabS9.
This behavior is probably due to the presence of excipients promoting
wettability in the TabFS9 formulation. However, compared to nano­
fibers (S9), that have lower thickness, TabFS9 values of contact angle are
slightly higher. Moreover, increasing drop contact time with solid sur­
face led to decrease contact angle values of TabFS9.
In Table 4 results of hardness test were reported.
Tablets showed similar strength of crushing values; TabFS9, prob­
ably due to the presence of external excipients, showed slightly higher
the S4, S5, S6 samples, containing PVP10 and Soluplus at different
concentrations, compared to MLX free drug, in all dissolution media
considered (Fig. 4).
However, the different percentage of Soluplus (20%, 30% and 40%
w/v), did not show the expected results, in fact, their release rate did not
show a significant improvement by increasing surfactant concentration
(data not reported).
Addition of SLS to the S4 sample thus obtaining S7, allowed to in­
crease the dissolution rate of MLX in all the dissolution media consid­
ered. Finally, S7 is able to release the entire dose of the drug in less than
2 h in three fluids considered (pH 1.0, pH 4.5 and deionized water), and,
in particular, pH 4.5 buffer and H20, MLX release was achieved in very
few minutes. Probably this interesting behavior of S7 was favored by the
small diameter of the fibers (440 ± 0.1 nm) by exposing a higher surface
area to the fluid and thanks to the presence of a second surfactant SLS
that enhanced drug wettability.
The S7 sample showed most promising results (Fig. 4), for this
reason, it was further improved by the addition of a higher percentage of
the active (3%w/v), S8, and by second surfactant SLS (1% w/v) to yield
S9 sample. S8 and S9 showed a further, progressive increase in disso­
lution rate of the drug in all the dissolution media considered, and S9
was able to release the entire dose in pH 4.5, H2O and pH 7.5 in less than
10 min (Fig. 5).
As expected, TabS8 and TabS9, obtained by compressing the grinded
nanofibers made from S8 and S9 samples, showed slower dissolution
rates, compared to the uncompressed nanofibers, certainly due to lower
surface area exposed to the dissolution medium and considerable
reduction of porosity compared to the nanofibers. However, the MLX

Table 3
Values of contact angles measured for MLX, S9, TabS9 and TabFS9 using dissolution tests aqueous buffers.
H2O Buffer pH 1.0 Buffer pH 4.5 Buffer pH 7.5

t0 t60sec t0 t60sec t0 t60sec t0 t60sec

MLX 126.2 ± 0.5 125.1 ± 1.2 118.6 ± 0.8 117.9 ± 2.2 121.6 ± 0.7 120.8 ± 1.5 126.6 ± 0.2 124.1 ± 1.4
S9 26.5 ± 6.1 9.4 ± 5.3 23.3 ± 6.3 10.7 ± 8.1 19.4 ± 6.3 13.1 ± 4.4 20.5 ± 3.6 11.2 ± 3.5
TabS9 47.5 ± 3.4 35.3 ± 4.4 45.2 ± 5.8 24.9 ± 4.3 34.2 ± 3.5 22.9 ± 6.5 43.1 ± 4.6 27.3 ± 7.6
TabFS9 32.1 ± 4.0 21.2 ± 2.4 27.4 ± 3.3 18.6 ± 4.9 25.7 ± 2.4 18.2 ± 3.3 25.2 ± 3.8 16.3 ± 3.5

5
S. Pisani et al.
Fig. 4. In vitro dissolution profiles of free Meloxicam (MLX) and MLX from electrospun matrices obtained by combining Polyvinylpyrrolidone (PVP10) and Soluplus
(SOL) loaded with 1.5% w/v of MLX and Polyvinylpyrrolidone (PVP10), Soluplus (SOL) and sodium lauryl sulfate (SLS) loaded with 1.5% w/v of MLX in different
media: pH 1.0, pH 4.5, deionized water (pH 6.7) and pH 7.5. All samples contained 7.5 mg of MLX.
dissolution rate from TabS8 and TabS9 was improved compared to MLX
free drug in all dissolution media considered. Finally, TabS9 released the
whole dose in pH 4.5 buffer and H2O in about 120 min.
Furthermore, MLX dissolution rate from TabS9, TabFS9 and Mobic
was compared in the four different aqueous buffers (Fig. 6).
In pH 1.0 and pH 4.5 buffer solution, a higher percentage of drug
dissolved is obtained from TabFS9 compared to TabS9 and Mobic
commercial reference. In water the dissolution profiles of TabFS9, TabS9
and Mobic are comparable and much faster than the free drug. In pH 7.5
buffer, the fastest release rate is obtained from the commercial product
(complete dose delivered in about 20 min) followed by TabFS9 (dose
delivered in about 40 min), then TabS9 and finally the drug alone.
5. Discussion
This work investigated the possibility to use hydrophilic electrospun
nanofibers to enhance dissolution of the hydrophobic drug Meloxicam.
In the preliminary fibers optimization phase it was confirmed that by
increasing the amount (%w/v) of polymeric surfactant, Soluplus (SOL),
an increase in fibers diameter is obtained switching from nanometers
(using 20%w/v SOL and 30% w/v SOL) to micrometers (40%w/v SOL).
Fibers in a nanometer size range were preferred due to their higher
surface area available for contact with dissolution aqueous buffer.
Moreover, MLX dissolution rate from S4 nanofibers exhibited greater
behavior compared to S5 and S6 samples. For these reasons, formulation
6
Journal of Drug Delivery Science and Technology 66 (2021) 102878
S4 (20%w/v PVP10 + 20%w/v SOL + 1.5%w/v MLX) having fibers
dimension of 330 ± 0.14 nm, was selected for further optimizations.
Addition of MLX (1.5%) to formulations didn’t remarkably influence
fibers dimension compared to placebo fibers.
Considering MLX dissolution rate from fibers obtained using sample
S4, a second surfactant (SLS 1%w/v) was added to further enhance the
dissolution rate of MLX. The fibers obtained using formulation S7 (20%
w/v PVP10 + 20%w/v SOL + 1%w/v SLS + 1.5% MLX) still showed
dimensions in a nanometer size range (440 ± 0.10 nm) and interesting
results in terms of MLX dissolution rate in all the buffer solutions tested
in comparison to all other fibers (formulation devoid of SLS i.e. S4, S5
and S6) and free drug MLX.
Another modification was made to promote dissolution profile of
MLX and was the increasing of MLX percentage dose (3%w/v). Imple­
mentation of MLX content didn’t remarkably influence fibers dimension
in all cases tested (S8 and S9), remaining in a nanometer size range.
Considering the dissolution profile of MLX from the fibers obtained
from formulation S7 and formulation S9 was possible to notice that the
drug dose was released completely in deionized water in very few mi­
nutes and in short times also in pH 7.5 buffer.
As expected, MLX dissolution profiles from the tablets are slower
compared to dissolution profiles from the corresponding electrospun
nanofibers due to the larger surface area exposed to the fluid and higher
porosity of nanofibers. However, a suitable dissolution performance is
obtained from TabF9 in pH 4.5 buffer and deionized water, which is
S. Pisani et al.
Fig. 5. In vitro dissolution profiles of S8, and S9 electrospun matrices compared to the corresponding tablets TabS8 and TabS9, in pH 1.0, pH 4.5, deionized water
(pH 6.7) and pH 7.5; free MLX is reported as reference. All samples contain 7.5 mg of MLX.
much higher compared to that of the free drug.
The formulation (TabFS9) showed better wettability behavior and
dissolution profile in all the buffer tested compared to TabS9. Interesting
results were obtained comparing the dissolution profiles of TabFS9 to
Mobic commercial product; in vitro dissolutions performed in buffers pH
1.0, pH 4.5 and deionized water registered a faster MLX dissolution
profile from TabFS9 rather than Mobic. In buffer pH 4.5, TabFS9 and
TabS9, showed faster MLX dissolution profiles compared to Mobic
while, in deionized water, the dissolution profiles of TabS9 and Mobic
are comparable.
Considering cases reported in literature, MLX loaded-PVP30 nano­
fibers formulated by Varma et al., obtained 73% of MLX released in
buffer pH7.5 within 30 min (Varma et al., 2013). Instead MLX loaded-
PVP10:SOL:SLS nanofibers (S9) proposed in this work, reached a 80% of
the dose released in buffer pH 7.5 already after 20 min. Our formulation
could be used as a more suitable carrier to enhance MLX solubility.
6. Conclusion
To conclude, the results obtained in this study demonstrated that the
proposed 20%w/v PVP10 + 20%w/v SOL +1%w/v SLS electrospun fi­
bers, loaded with 3%w/v MLX, caused a significant increase of the sol­
ubility rate of the poorly water-soluble drug MLX. Dissolution test
performed in four different buffers, to mimic physiologic conditions,
proved the enhanced dissolution rate of MLX from the electrospun fibers
compared to free drug, in all buffers tested. Further improvement in
7
Journal of Drug Delivery Science and Technology 66 (2021) 102878
MLX dissolution performances was reached formulating the product
with other excipients promoting wettability as demonstrated with
TabFS9. Comparing the results obtained from TabFS9 with the com­
mercial form (Mobic®), an improvement in MLX dissolution rate was
achieved in three different aqueous media (pH 1.0, pH 4.5 and deionized
water) and good results were also obtained in buffer pH 7.5 after 40 min,
suggesting that the proposed tablets could be used as valid oral dosage
form to enhance MLX dissolution rate and bioavailability.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Author contributions
Conceptualization, formal analysis and writing: Silvia Pisani; Data
curation, formal analysis and writing: Valeria Friuli; supervision: Gio­
vanna Bruni; Supervision and review & editing: Bice Conti; Supervision
and Project Administration: Lauretta Maggi.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
S. Pisani et al.
Fig. 6. In vitro dissolution profiles of tablets containing fibers alone of the S9 sample, TabS9, and TabFS9, tablets of the formulation with S9 sample in pH 1.0, pH 4.5,
deionized water (pH 6.7) and pH 7.5 compared with free MLX and the commercial product, Mobic. All samples contain 7.5 mg of MLX.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jddst.2021.102878.
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