International Journal of Pharmaceutics 477 (2014) 643–649

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International Journal of Pharmaceutics

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

Preformulation study of fiber formation and formulation of

drug-loaded microfiber based orodispersible tablets for in vitro
dissolution enhancement
Péter Szabó a,b , Barnabás Kállai-Szabó a , István Sebe b , Romána Zelkó b, *
a
Gedeon Richter Plc., Formulation R&D, Gyomroi Str. 19-21, Budapest H-1103, Hungary
b
University Pharmacy Department of Pharmacy Administration, Semmelweis University, Hogyes Endre Str. 7-9, Budapest H-1092, Hungary

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

Article history: Preformulation study of rotary spun hydroxypropyl cellulose fibers was carried out using the
Received 10 October 2014 combination of textural characterization of gels in the concentration range of 42–60% w/w and optical
Received in revised form 3 November 2014 microscopic evaluation of formed fibers. High adhesiveness values resulted in bead formation at lower
Accepted 5 November 2014
polymer concentration, meanwhile fiber formation was hindered when high adhesiveness values were
Available online 6 November 2014
associated with high polymer content. The optimum gel concentration for fiber formation was given to
50% w/w.
Keywords:
Drug loaded microfibers were prepared using a model drug of biopharmaceutical drug classification
High-speed rotary spinning
Microfibers
system class II. Fibers were milled, sieved and mixed with tableting excipients in order to directly
Hydroxypropyl cellulose compress orodispersible tablets. Hardness, friability, in vitro disintegration time values complied with
Orodispersible tablet the pharmacopoeial requirements. In vitro dissolution profiles obtained from three distinct dissolution
Dissolution enhancement media (pH 1.0; 4.5; 6.8) were quite differentiated compared to the compressed physical mixture of the
same composition. Difference and similarity factors confirmed that the drug dissolution from microfiber
based formula was almost independent from the pH value of the media. X-ray diffraction patterns
indicated that the drug embedded in microfibers was in amorphous state, and the decrease of o-Ps
lifetime values suggested that fiber formation enabled the development of a more ordered fibrous
system.
ã 2014 Elsevier B.V. All rights reserved.

1. Introduction no in vitro–in vivo correlation can be found due to the low

The spread of combinatorial chemistry and high throughput
screening in the pharmaceutical research have led to increased
amount of drugs with higher molecular weight, higher lip-
ophilicity, and poorer water solubility (Lipinski, 2000). The
undesirable physicochemical characteristics of new drug candi-
dates can be attributed to the presence of the phenomenon of
molecular obesity (Hann and Keseru, 2012). Regarding their
disadvantageous ADME behavior, the increasing proportion of
new drug candidates with poor water solubility poses challenge for
the pharmaceutical industry. According to the biopharmaceutical
drug classification system, active pharmaceutical ingredients in
class II and in class IV can be characterized by low water solubility.
While in case of chemical entities in class II in vitro–in vivo
correlation can be expected, in case of drugs in class IV limited or
* Corresponding author. Tel.: +36 1 2170927; fax: +36 1 2170927.
E-mail address: zelko.romana@pharma.semmelweis-univ.hu (R. Zelkó).
permeability (Amidon et al., 1995). Even though it is reported that
the in vitro dissolution enhancement of pharmaceutically active
compounds of class II is not necessarily resulted in the consequent
improvement of bioavailability, the most widely accepted formu-
lation approach of these drugs focuses on the facilitation of in vitro
dissolution (Sarnes et al., 2014).
Different techniques are used in the formulation processes of
drugs of poor water solubility in order to increase their solubility,
and thereby their bioavailability in peroral dosage forms. Over the
last decade hot-melt extrusion has gained popularity as a possible
way in the formulation of drugs of poor solubility and as a result of
its limited bioavailability (Repka et al., 2007). Other approaches
focusing on particle size reduction have also become important,
thus nanotechnology has emerged as the most promising
discipline. Several nanosized drug delivery systems were devel-
oped in order to improve solubility, bioavailability, tolerability,
toxicity of drug candidates such as micelles, microspheres,
dendrimers, solid–lipid nanocarriers, and self-emulsifying drug
delivery systems (Agrawal et al., 2014).

http://dx.doi.org/10.1016/j.ijpharm.2014.11.011
0378-5173/ ã 2014 Elsevier B.V. All rights reserved.
644 P. Szabó et al. / International Journal of Pharmaceutics 477 (2014) 643–649
Drug loaded polymer fibers are also intended to enhance the
solubility of poorly soluble drugs. Various spinning techniques are
used in the production of polymer fibers. The most frequently
applied method is electrospinning, where the fiber formation from
polymer solutions is induced by high voltage (Huang et al., 2003).
Other techniques such as melt spinning, high speed rotary
spinning are also suitable for manufacturing polymer-based nano-
and microfibers (Badrossamay et al., 2010; Nakata et al., 2007; Sebe
et al., 2013). Polymeric fibers have several favorable properties,
such as high specific surface area, high porosity and the ability to
include the active pharmaceutical ingredient in amorphous state
(Huang et al., 2003; Verreck et al., 2003). However interest in fiber-
based formulations have been growing recently due to their
potential applicability in release-modification and solubility
improvement (Okuda et al., 2010; Verreck et al., 2003; Yu et al.,
2010), the main interest focuses on parenteral and topical dosage
forms, while hardly any attention is given to formulations intended
for oral administration.
In high speed rotary spinning technique, the formed centrifugal
force and the solvent evaporation give rise to the fiber formation.
The applied rotary speed, the composition of the polymeric
solution and the inner diameter of the wall orifices are the main
parameters which affect the microstructure of the fibers (Badros-
samay et al., 2010). Both electrospinning and high speed rotary
spinning are capable for production of micro- and nanofibers.
While conventional electrospinning process is limited by its low
productivity, with high speed rotary spinning fibers can be
produced with a higher rate. Although the lowest the fiber
diameter the highest the specific surface, which is beneficial for the
dissolution, the processibility of nano-sized drug delivery systems
can be cumbersome. A typical example for this problem is the
production of tablets from fibers which must be milled in order to
blend them with conventional tableting excipients of a size range
of a few micrometers. Huge particle size differences can be resulted
in segregation and consequently inhomogeneity of tablets
(Williams, 1976).
In recent years, research on the formulation of orodispersible
tablets has become very popular due to their pharmaceutical and
therapeutic benefits. The easy administration, the rapid liberation,
and the increased bioavailability of the incorporated drug are the
most important properties which can be effectively utilized in the
formulation of drugs (Bandari et al., 2008).
Hydroxypropyl cellulose is considered as common pharmaceu-
tical excipient, since it has a wide application area in both solid,
semisolid and fluid dosage forms (thickening, coating, emulsifying
agent). The advantageous solubility properties of the polymer, it is
soluble in both water and in organic solvents, make its usage a
reasonable choice in the formulation of drugs of poor water
solubility. The fundamental assumption was based on the common
dissolution medium of the polymeric base and the active
ingredient. The latter was also dissolved in organic solution thus
forming a homogeneous polymeric gel for fiber formation with
high speed rotary spinning technique, which could have an impact
on the dissolution of the drug.
Versatility of texture analysis is leading to its increasing
importance in the measurement of textural properties of different
dosage forms. The method is capable for the characterization of
solid, semi-solid, and fluid systems. In a previous paper authors
showed that measuring textural properties is a good alternative to
obtain rheological and mechanical information either about liquid
crystalline and solid fibrous systems (Szabó et al., 2014).
The aim of this study was to track the fiber formation of
hydroxypropyl cellulose using gels of different concentrations and
elucidate the texture-structure relationship. Furthermore, we
intended to demonstrate the importance of the high speed rotary
spinning technique in the formulation of the poorly soluble drugs
using a model drug substance. The produced drug-loaded micro-
fibers were proposed to be processed in order to develop
orodispersible tablets.
2. Materials and methods
2.1. Materials
Hydroxypropyl cellulose (Klucel1 ELF, Mw
40,000, moles of
substitution of 3.8, Ashland, USA), citric acid monohydrate (Molar
Chemicals, Hungary) was used in the fiber formation process. A
semisynthetic alkaloid derivative model drug was selected from
the biopharmaceutical classification system class II and can be
characterized with the following physicochemical properties:
Mw < 500, pKa = 7.1 (with one basic centre), water solubility < 5.1
mg/ml, logP 4–5. In the preparation of the drug stock solution
diluted ethanol (3:1 volume ratio) was made by the mixing of
75 ml of ethanol (96% v/v%, Reanal, Hungary) and 25 ml of distilled
water. Potassium dihydrogen phosphate (Molar Chemicals,
Hungary), sodium hydroxide (Molar Chemicals, Hungary), and
distilled water were applied in the preparation of the dissolution
media. The excipients of the orally disintegrating tablets were as
follows: microcrystalline cellulose (Vivapur1 102 MCC) as filler
and disintegrant, mannitol (Mannogem1 EZ, SPI Pharma) as filler,
milled polyethylene glycol 1500 (Macrogol 1500, Hungaropharma)
as lubricant, equimolar mixture of milled citric acid anhydrate, and
sodium bicarbonate as effervescent agent and croscarmellose
sodium (Vivasol1, JRS Pharma) as superdisintegrant.
2.2. Preparation of drug stock solution
5.000 g of model drug was measured into a 50.00 ml volumetric
flask, and then it was suspended with about the half of the
necessary amount of diluted ethanol (3:1 volume ratio). When a
lactescent dispersion was formed, 3.000 g of citric acid mono-
hydrate was added. The dispersion was carefully shaken until a
clear solution was obtained, then the solution was diluted to
50.00 ml with the solvent mixture.
2.3. Preparation of hydroxypropyl cellulose gels
Hydroxypropyl cellulose gels were prepared in a beaker by
addition of the necessary amount of distilled water. After careful
homogenization, the samples were covered with paraffin tape and
stored at room temperature (T = 25  C) for one hour. These samples
were used in the preparation of the fibers by high-speed rotary
spinning. 15 min before the beginning of the texture analysis 10 g of
each sample was put in a small cylindrical glass container (internal
diameter: 23 mm, height: 30 mm), which was fixed to the basis of
the texture analyzer. Hydroxypropyl cellulose gels of 42–60% w/w
concentrations were prepared for the texture analysis. Based on
the results of the texture analysis the optimum polymer
concentration was 50% w/w therefore gels containing model drug
was prepared by the addition of the same amount of Klucel ELF
hydroxypropyl cellulose and model drug stock solution. After
careful homogenization the gels were covered with paraffin tape,
and stored at room temperature (T = 25  C) for one hour.
2.4. Texture analysis
Three parallel gel samples of each concentration were analyzed
using Brookfield CT3 Texture Analyzer with 4500 g load cell
(Brookfield Engineering Laboratories, Inc., USA). The test was
performed with a cylindrical probe (TA-5, black delrin, diameter:
12.7 mm, length: 35 mm). The compression type test was carried
out performing one cycle. The pretest speed, test speed, and the
 P. Szabó et al. / International Journal of Pharmaceutics 477 (2014) 643–649 645

return speed were set to 2, 1 and 1 mm/s. A force of 2 g was used as
trigger load, after reaching the trigger load the probe compressed
the gels through a depth of 10 mm. The sampling rate was
20 points/s, and Brookfield Texture Pro CT software was used for
evaluation. The adhesiveness which is the total negative area of the
load-distance curve of the first cycle was determined (Szabó et al.,
2014).
2.5. High-speed rotary spinning technique
For producing fibers high-speed rotary spinning technique was
performed, where the samples were put in a perforated rotating
reservoir, which is made of aluminum. The rotating reservoir was
powered by a motor WSE 602 M (AEG, Germany), and the fiber
formation was carried out at 10,500 RPM. The rotational speed was
controlled with a toroidal transformator and determined with
laser revolution counter (DT-10L, Voltcraft, Germany). The internal
diameter of the two side wall orifices were 0.5 mm.
2.6. Optical microscopic morphology study
Optical microscope (LCD Micro type; Bresser; Germany and
Nikon SMZ 1000 type; Nikon, Tokyo, Japan) was used to monitor
the fiber formation and measuring the average fiber diameter.
Magnifications were: 40, 100. The produced digital images were
analyzed using the computer program Image Pro Plus 4.5 (Media
Cybernetics, Bethesda, U.S.). A standard micrometer scale was used
for the calibration. Minimum of 20–25 fibers could be photo-
graphed at a time. Fifty measurements were taken and average
fiber diameter was obtained from values of diameter of 50 different,
individual fibers.
2.7. Milling process
Citric acid anhydrate, sodium bicarbonate, polyethylene glycol
1500, and the microfibers were milled with a Gorenje SMK 150B
grinder for 6 min with 24,000 rpm (determined with DT-10L laser
revolution counter, Voltcraft, Germany). Afterwards, the milled
materials were sieved through a mesh sieve (nominal wire
diameter 320 mm).
and the so-called ortho-positronium atom (Suvegh et al., 1999).
Positron as the antiparticle of the electron lives only a few hundred
picoseconds in materials. However, several positrons form ortho-
positronium (o-Ps), a hydrogen-like exotic atom, before their
annihilation. These positrons live a “very long” time, usually a few
nanoseconds. In polymers the formed o-Ps atoms tend to be
trapped in free volume holes and their annihilation is not governed
by their intrinsic lifetime but by the electron density in the holes.
Their lifetime is associated with the size of the free volume around
them (Deng and Jean, 1993):
"
1 R 1 2pR 1
t ¼ 1 þ sinð Þ (2)
2 R þ DR 2p R þ DR
where t is the positronium lifetime, R the radius of the free volume
hole, and DR a constant. As a very crude guess, we can say that a
longer lifetime indicates a larger hole.
For positron lifetime measurements, a positron source made of
carrier-free 22NaCl was used. Its activity was around 105Bq.
Lifetime spectra were measured with a fast-fast coincidence
system based on BaF2/XP2020Q detectors and Ortec1 electronics.
Every spectrum was recorded in 4096 channels of an analyzer card
for 3  700 s and each contained about 1.5  106 coincidence
events. Three parallel spectra were measured at each composition
to increase reliability. After summarizing the parallels, spectra
were evaluated by the Resolution computer code (Kirkegaard et al.,
1981); the indicated errors are the deviations of the lifetime
parameters obtained. Three lifetime components were found in all
the samples.
The powder blend (physical mixture) consisting of 84.6% w/w
Klucel ELF hydroxypropyl cellulose, 5.4% citric acid monohydrate,
and 10% w/w model drug was measured as control of drug loaded
fibers.
2.10. UV–vis spectroscopic analysis
Drug content of milled fibers was determined using Agilent
8453 UV–vis Diode Array System (USA) and 0.1 M hydrochloric acid
as solvent. The drug content of the samples was measured on the
basis of the calibration curve recorded earlier. Five parallel
measurements were performed.

2.8. Determination of the particle size distribution

2.11. Powder X-ray diffraction

A laser scattering particle size distribution analyzer LA-950V2

For crystallinity study powder X-ray diffraction patterns of
(Horiba Co., Kyoto, Japan) was used with a dry feeder unit to
samples (fibers, physical mixture of same composition, and model
measure the particle diameter of the excipients, the physical
drug) were obtained by using X’Pert Pro diffractometer (PAN-
mixtures and the milled fibers in the range of 0.011–3000 mm. A
Analytical, Almelo, The Netherlands) system with Cu Ka I radiation
measurement was performed with the following parameters: air:
(l = 1.5406 Å) over the interval 2.0000–40.0014 . The measure-
0.1 MPa; feeder intensity (0–200):80; relative refractive index:
ment conditions were as follows: target of Cu; filter of Ni (thickness
1.60. The distribution values were the averages of 3 determinations
of each sample. The results represented as volume distribution of
3  5000 particles. To describe the width of the distribution span
Table 1
values were calculated according to Eq. (1) Composition of the investigated tablets: the microfiber based formula TF and

 control tablets made of its corresponding physical mixture, TPM.
D90%  D10%
S p an ¼ (1)
D50% Formulation series

where D10%,D50%, and D90% are the particle diameters at 10, 50, and Component (% w/w) TF TPM
90% of the cumulative particles undersize plot. The results are the Milled drug loaded microfiber 20 –
averages of five parallel measurements. Vivapur 102 28 28
Polyethylene glycol 1500 2 2
Vivasol1 3 3
2.9. Positron lifetime measurements Effervescent agenta 7 7
Mannitol 40 40
For the microstructural characterization of fibers positron Klucel ELF – 16.92
annihilation lifetime spectroscopy (PALS) was applied as a unique Model drug – 2
Citric acid monohydrate – 1.08
method since it is exceptionally sensitive to the free volume. The
measurement is based on the interaction of the free volume holes a
Equimolar mixture of milled citric acid anhydrate and sodium bicarbonate.
646 P. Szabó et al. / International Journal of Pharmaceutics 477 (2014) 643–649

Fig. 1. Optical microscopic tracking of fiber formation of hydroxypropyl cellulose gels of different concentrations. (A): 42; (B): 44; (C): 46; (D): 48; (E): 50; (F): 52; (G): 54; (H):
56; (I): 58; and (J): 60% w/w hydroxypropyl cellulose.

was 0.02 mm); voltage of 40 kV; current of 40 mA; angular step of 2.13. Tablet parameters
0.0334 ; counting time of 40.005 s.
5 tablets of each composition were measured by employing
2.12. Preparation of orodispersible tablets tablet hardness tester (8 M, Dr. Schleuniger Pharmatron,
Switzerland).
Orodispersible tablets with a weight of 500 mg of different
The friability of the tablets was determined by weighing ca.
compositions were prepared by direct compression technique
6.5 g of dedusted tablets and moved for 4 min with a revolution
according to the formula given in Table 1, where microfiber based
speed of 25 rpm in an Erweka friability tester (TAP, Offenbach/
tablets were assigned as TF, and control tablets consisting physical
Main, Germany). The percentage friability was calculated by the
mixture of hydroxypropyl cellululose and model drug were
reweighting of the dedusted tablets.
assigned as TPM. All of the excipients were sieved through a
mesh sieve (nominal wire diameter 320 mm). In order to provide In vitro disintegration times were determined by using Erweka
the specified quantity of model drug (10 mg) in each tablet the Disintegration Tester (ZT 4, Germany). The applied media was
necessary amount of milled microfibers were corrected by their 900 ml of demineralised water; the measurement was carried out
drug content obtained by the assay against the amount of the at 37  2  C by visual observation. Six tablets from each composi-
microcrystalline cellulose. tion were evaluated for their disintegration times. The observed
The substances were homogenized in a Turbula (T2F model; minimum and maximum values are reported in results and
Willey A Bachofen AG, Maschinenfabrik, Basel, Switzerland) using discussion.
a 1200 ml cylindrical container at 23 rpm for 30 min. Tablets were
prepared by a single-punch tableting machine (Diaf TM20,
2.14. Dissolution test
Copenhagen, Denmark), with a shallow concave round punch of
13.5 mm. In order to produce tablets of a specified hardness
Dissolution tests of the orodispersible tablets were carried out
(30–35 N) the applied pressures were adjusted for each formula.
in a Hanson SR8-Plus (Hanson Research, Chatsworth, USA) type
dissolution tester. The temperature of the dissolution fluid was
37  1  C and the rotation speed was 50 rpm, using rotating
paddles. The tests were made with three different dissolution
Table 2
mediums: 500 ml of a solution of hydrochloric acid of pH 1.0 (Ph.
The average fiber diameters of prepared microfibers.
Eur. 8.), 500 ml of a phosphate buffer of pH 4.5 (Ph. Eur. 8.) and
Sample % w/w polymer Average fiber diameter (mm) 500 ml of a phosphate buffer of pH 6.8 (Ph. Eur. 8.). 3.00 ml of
48 (aqueous) 13.5  6.1 samples were taken at predetermined time points using a Biohit
50 (aqueous) 11.8  3.3 Proline 5.00 ml pipette. The samples were filtered through a 10 mm
52 (aqueous) 13.0  5.0
UHMW polyethylene cannula dissolution filter. The model drug
54 (aqueous) 15.5  3.7
50 (ethanolic, containing drug) 12.6  4.8 content of the samples was measured with an UV–vis spectropho-
tometer (Agilent 8453 UV–vis Diode Array System, USA) at the
 P. Szabó et al. / International Journal of Pharmaceutics 477 (2014) 643–649 647

ensure sameness or equivalence of the two curves and, thus, of the

performance of the test and reference samples.

3. Results and discussion

Aqueous Klucel ELF type hydroxypropyl cellulose gels within a

concentration range of 48–54% w/w have proved suitable for fiber
formation with high speed rotary spinning. In case of 42% w/w only
bead formation was observed, while only limited fiber formation
with numerous beads was detected at concentration range of 46–
48% w/w. Furthermore the yield of the fiber production was
dramatically reduced using gels of concentration 56–58% w/w
(average yields were as follows: 48% w/w: 30%, 50% w/w: 40%, 52%
w/w: 20%, 54% w/w: 30%, 56% w/w: 5%, 58% w/w <5% for dry
content). Fibers produced from gel of 56–60% w/w were sticky.
Fig. 1 represents the microscopic appearance of fibrous samples
prepared from the gels of the investigated concentrations. Average
fiber diameters are shown in Table 2. In accordance with other
research papers helical twisted domains of microfibers could be
also found during microscopic analysis, which can be contributed
Fig. 2. Changes of adhesiveness as a function of hydroxypropyl cellulose
concentration of gels.
to the formed liquid crystalline structure (Canejo et al., 2008;
Szabó et al., 2014).
characteristic wavelength of the model drug on the basis of the Since, hydroxypropyl cellulose tends to form liquid crystalline
calibration curve recorded earlier. solutions, and the phenomenon depends on the polymer
concentration, it could be expected that the supramolecular
2.15. Comparison of the dissolution curves ordering of the polymer chains has an impact on the rheological
characteristics of the gel (Ernst and Navard, 1989; Werbowyj and
Mathematical comparison of the drug release profiles of Gray, 1984). It is also reported in a previous paper, that textural
different compositions in each media was carried out by characterization is useful in the tracking of lyotropic structure
calculating the difference (f1) and similarity (f2) factors according related rheological changes, which is essential in respect of fiber
to Eqs. (3) and (4) proposed by Moore and Flanner (Moore and formation (Szabó et al., 2014). Fig. 2 represents the results of
Flanner, 1996) and implemented by FDA CDER. texture analysis. It can be seen, that the adhesiveness of gels drops
The two factors are: at concentration 50–52% w/w, afterwards the curve sharply
reaches higher values. Based on the textural characterization of
n0
St¼1 k Rt  T t k Klucel EXF hydroxypropyl cellulose, which has twice an average
f1 ¼ n0
 100 (3) molecular weight as Klucel ELF, we could suggest that the lower
St¼1
the adhesiveness the more beneficial the spinability of these gels
(Szabó et al., 2014). Similar correlation was presented in recent
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi paper, where Klucel EXF was investigated. These results imply that
n0
S ðRt  T t Þ2 the optimum concentration of the applied polymer is 50% w/w. It is
f 2 ¼ 50  log 1 þ t¼1  100 (4)
n0 also confirmed by the average diameter values, and the productiv-
where n is the number of time points, R is the dissolution value of ity of the method, since the former was smallest and the latter was
the reference sample at time t (compressed physical mixture), and the highest (ca. 40% for dried content). Regarding the changes in
T is the dissolution value of the test sample at time t (microfiber adhesiveness in the concentration range of 50–54% w/w it could be
based formula). For curves to be considered similar, f1 values assumed that the liquid crystalline structure of gels of 50 and 54%
should be close to 0, and f2 values should be close to 100. Generally, w/w differs, which affected the fiber morphology and yield of the
f1 values up to 15 (0–15) and f2 values greater than 50 (50–100) method.

Fig. 3. Optical microscopic morphology of rotary spun drug loaded hydroxypropyl cellulose microfibers viewed at different magnifications, (A): 40, (B): 100 magnification.
648 P. Szabó et al. / International Journal of Pharmaceutics 477 (2014) 643–649

Table 3 Table 5
Particle characteristics of the milled microfiber and the milled excipients. Difference (f1) and similarity (f2) factors calculated according to Eqs. (1) and (2).

Milled substance Mean size (mm) Size distribution span Test

Microfibers 208  10 2.67  0.19 TF
Citric acid anhydrous 174  58 3.23  0.72
Polyethylene glycol 1500 146  12 1.44  0.14 f1 f2
Sodium bicarbonate 132  1 1.78  0.01 pH 1.0 pH 4.5 pH 6.8 pH 1.0 pH 4.5 pH 6.8
Reference TPM
pH 1.0 11.36 15.56 11.38 45.17 44.66 50.77
pH 4.5 123.33 88.59 97.90 17.42 24.22 22.42
Table 4 pH 6.8 323.98 258.02 275.71 10.15 14.62 13.42
Tablet parameters of the investigated orodispersible tablets.

Tablet parameters TF TPM

Hardness (N) 32.2  1.3 32.0  1.9

Friability (% w/w) 0.39 0.37
Disintegration time (s) 25.18 26.72 25.25
Mass (g) 0.5008  0.0061 0.5029  0.0022
The microscopic appearance of the rotary spun drug loaded fibers
shows a clear, transparent fibrous structure with no observable
beads (Fig. 3). The average fiber diameter obtained from the image
analysis was 12.6  4.8 mm.
In order to obtain a homogeneous powder blend for the direct
compression of tablets, the particle size distributions of milled
fibers and excipients were determined. Table 3 summarizes the
results of the particle size measurements of the milled fiber and
grinded excipients. The results indicate that there was no
considerable difference between the fibers and excipients there-
fore it was supposed that homogeneous tableting mixture could be
prepared.
The drug content of the microfibers was 8.99  0.13% w/w based
on five parallel measurements. This is a relative high drug content
among drug loaded fibers. Regarding the average diameters of
fibers it can be seen that the presence of the drug has not
significantly influenced the morphology.
It can be seen from Table 4, that all of the measured tablet
parameters comply with the pharmacopeial requirements (Ph. Eur.
8., USP 37). All of the orodispersible tablets disintegrated within
30 s in a relatively narrow time range.
Fig. 4 represents the drug release profiles of different
formulations carried out in distinct dissolution media. Table 5
summarizes the calculated difference and similarity factors. As can
be seen from Fig. 4 and Table 5 the model drug release from the
control orodispersible tablets compressed from physical mixture
depends on the pH value of the applied dissolution media. While in
case of 0.1 M hydrochloric acid there is no significant difference
between the orodispersible tablets, the curves obtained at pH
29.31
6.8 are quite differentiated. More than twice amount of active
ingredient released at pH 6.8 from the fiber-based tablets than
from the directly compressed physical mixtures of the same
composition. The release profiles of Fig. 4 clearly demonstrate the
great difference which is also confirmed by the difference and
similarity factors. To understand the reason behind the phenome-
non X-ray powder diffraction patterns (Fig. 5) were recorded and o-
Ps (Fig. 6) lifetimes were measured. The results presented in Fig. 5
indicate that there is a significant difference between drug loaded
microfibers and the physical mixture of the same composition in
respect of free volume holes. Based on these results we can suggest
that as a consequence of the formation of secondary binding forces
the orientation of the polymeric chains has altered that was
tracked by the decrease of the free volume holes. The obtained X-
ray patterns demonstrate that the drug embedded in microfibers
was in amorphous state, while it was crystalline in the physical
mixture, since similar peaks can be seen in the X-ray patterns of
model drug and physical mixture. The latter can be explained by
the crystalline structure of model drug, which scatters X-rays in
certain directions, thus resulting high intensity peaks. Along with
the fiber formation the polymeric chains were getting ordered
meanwhile crystalline-amorphous transition of the model drug
occurred. On the other hand the presence of citric acid in
microfibers also plays an important role in the dissolution
enhancement, but we could suggest that the effect of the acidic
compound could not be contributed solely to the changes of the pH
of the microenvironment. It is assumed; in accordance with other
research paper that citric acid acts as a solid plasticizer via forming
secondary bonds with the hydroxyl groups of hydroxypropyl
cellulose resulting the alternation of the ordering of polymeric
chains. The latter is consistent with the findings of o-Ps lifetime
measurements. This supramolecular ordering was confirmed by
the decrease of the o-Ps lifetime values. The formation of the
amorphous state could be the consequence of the altered
supramolecular structure.

Fig. 4. In vitro dissolution analysis of orodispersible tablets carried out at dissolution media of three distinct pH values: (A): pH 1, (B): pH 4.5, and (C): pH 6.8.
 P. Szabó et al. / International Journal of Pharmaceutics 477 (2014) 643–649
Fig. 5. X-ray diffraction patterns of the investigates substances: milled drug loaded
microfiber, physical mixture of the same composition, model drug.
Fig. 6. Ortho-positronium lifetime (o-Ps) values of the investigated samples: milled
drug loaded microfibers, and physical mixture of the same composition.
4. Conclusion
In summary, this study demonstrates the importance of
microfiber based drug delivery systems in the formulation process
of drugs of biopharmaceutical drug classification system class II,
opening new horizons in pharmaceutical development. The
novelty of our research lies in the formulation of solid oral dosage
form of drug loaded microfibers. Since the drug embedded in
microfibers was in amorphous state, and the supramolecular
ordering of polymeric chains of hydroxypropyl cellulose altered
due to the fiber formation process, the microfiber based formula
had significantly better in vitro dissolution characteristics, than the
compressed physical mixture of the same composition. Preformu-
lation study using textural characterization enabled the determi-
nation of optimum gel concentration regarding the fiber formation.
649
Dissolution profile of drug loaded microfiber based orally
disintegrating tablets was not affected by the pH of the
dissolution media, thus enabling the drug absorption from the
whole gastrointestinal tract, which could have an impact on
bioavailability.
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