Comparison of Amorphous Solid Dispersions of Spironolactone
Prepared by Spray Drying and Electrospinning: The Influence of the
Preparation Method on the Dissolution Properties
Introduction The number of effective drug candidates is increasing year by year
with the advancement of drug discovery strategies such as high throughput
screening, combinatorial chemistry, or the application machine learning. − However, the majority of the promising active pharmaceutical ingredients
(APIs) are characterized by poor water solubility, which results in several difficulties during the formulation
of oral solid dosage forms. Different formulation strategies are available
to enhance the dissolution properties without modifying the structure
of the poorly water-soluble drugs , One of the
most common physical modifications is the formulation of amorphous
solid dispersions (ASDs). Molecularly
dispersed APIs in the polymer matrices result in higher dissolution;
therefore, increasing the bioavailability of the drug. Numerous
technologies have been developed during the last few decades
for the preparation of ASDs with high productivity and efficiency.
As a result, more and more ASD-loaded products have entered the pharmaceutical
market, which proves the feasibility of this formulation strategy. In general, ASD preparation methods are classified
into three groups, namely the solvent-based methods, the melt (or
fusion) methods, and mechanochemical activation (e.g., ball milling)
methods. The preparation method can influence
the dissolution, − the bioavailability, the downstream processing, and the
stability of the ASDs. , Furthermore, the properties of
the APIs can also determine the applied downstream methods and used
excipients. − Half of the FDA-approved ASD-loaded products
are prepared by the
solvent-based methods, which is a particularly
good choice in the case of thermosensitive APIs. The majority of the
marketed products are prepared by spray drying since it is a simple
and effective technique for preparing ASDs. , Although the application of temperatures above the melting points
is not needed, the removal of residual solvents is a huge challenge
in solvent-based techniques. On the one hand, there are strict quality
requirements related to the limit of the residual solvents, especially
the organic solvents. On the other hand,
the moisture uptake of some hydrophilic polymers decreases the glass
transition temperature, which has a high correlation with the deterioration
of dissolution properties and stability. − In this context,
different drying kinetics can be observed for various solvent methods,
and thus the quality and the main properties of the products are also
distinct. − In the case of certain drug–polymer solutions
and methods, the solvent evaporation rate is not fast enough, and
thus ASDs with a nonideal structure are formed. Consequently, phase separation and crystallization start, which may lead to a decrease in the dissolution. To handle these problems, several novel techniques
have been developed during the last decades such as electrospinning,
electroblowing, and electrospraying. − Besides, electrostatic force-based methods usually require less
solvent, highly viscous solutions, and allow very gentle and fast
solvent evaporation. Compared to the commonly used spray drying, electrostatic
force-based techniques proved to be a more reliable method in many
cases to avoid phase separation in ASDs. , , Spironolactone (SPIR) is a suitable
model drug used to compare
high-productivity technologies of electrospinning and spray drying.
SPIR is an antihypertensive and diuretic API with poor water solubility,
and it is a widely used model drug in ASDs. Several research papers
have been published about successful dissolution enhancement of SPIR
via solvent-based or melt methods. − SPIR possesses five hydrogen-bond
acceptor groups, and the application of polymers containing hydrogen-bond
donor groups may result in drug–polymer interactions in the
ASD, leading to improved physical stability. , Consequently, the influence of the polymer type on the dissolution
of SPIR needs to be considered. , This work aimed
to compare two different solvent-based methods
thus a noninteracting system was chosen to eliminate complex interactions
caused by hydrogen-bonding. For this purpose, poly(vinylpyrrolidone- co -vinyl acetate) (PVPVA64) was used as a polymer matrix,
which has only hydrogen-bond acceptor groups similar to the SPIR . This model system
makes it possible to evaluate the effects of the particle shape, the
drying rate, and the electrostatic field. To the best of our knowledge,
the comparison of spray drying and electrospinning under similar processing
conditions and using the same apparatus has not yet been performed.
It was expected that such a comparison would highlight the relevance
of the preparation method selection, aiming to satisfy the physical
stability requirements related to ASDs. 

Materials and Methods 2.1 Materials Micronized SPIR (Form II)
( a) (melting
point: 211 °C) was received from Gedeon Richter Plc. (Budapest,
Hungary). PVPVA64 (Kollidon VA64) ( b) was kindly provided by BASF (Ludwigshafen,
Germany). Dichloromethane (DCM) and absolute ethanol (EtOH) were analytical
grade, and both were purchased from Merck Ltd. (Budapest, Hungary)
and used without any further purification. For the dissolution tests,
37 w/w % HCl was ordered from Merck Ltd. (Budapest, Hungary). 2.2 Sample Preparation A multifunctional
apparatus was used to prepare SPIR-loaded ASDs  to reduce technological differences. , The equipment was originally developed for electrospinning, but
it can be perfectly operated as a rotary spray dryer. The key element
of the machine is a round-shaped, stainless steel spinneret with orifices
( d spinneret = 34 mm, d orifice = 330 μm), connected to a high-speed motor.
The rotational speed of the spinneret was set to 40 000 rpm
during both experiments. ASDs were prepared at ambient temperature
(25 °C) and 45 ± 5% relative humidity. A grounded stainless
steel cone at the bottom of the drying chamber was used. The products
were periodically removed from the grounded metal cone with automated
air knives (pressurized blowing air) and were collected in a cyclone,
which enabled the application of the system in continuous manufacturing
mode. A previously determined drug–polymer ratio was used for
electrospinning with 40% SPIR and 60% PVPVA64. The solvent mixture consisted of dichloromethane and ethanol,
which were already tested for high-speed electrospinning of itraconazole. During spray drying, a less viscous solution
was used than that in the case of electrospinning experiments. summarizes the exact
amount of raw materials used and the sample codes. The solutions were
fed into the spinneret with a Watson–Marlow peristaltic pump
(Watson–Marlow Fluid Technology Group, Budapest, Hungary).
The applied feeding rates were 300 and 600 mL/h in the case of the
electrospinning and spray drying, respectively. For fiber formation,
40 kV positive, a direct current voltage was applied to the grounded
stainless steel spinneret during electrospinning. The electrospun
(ES) product was pushed through a sieve with a hole size of 0.8 mm
after the preparation to achieve a more uniform macroscopic particle
size. The influence of the drying kinetics was also
examined through
the preparation of samples by film casting. The solution of SPIR and
PVPVA64 was cast into square-shaped silicon molds (3 × 50 ×
50 mm 3 ) and dried for 3 days at room temperature. The thickness
of the film was 70 ± 5 μm, which was determined with a
Pro-Max Electronic Digital Caliper (NSK, Tokyo, Japan). The film was
ground into small pieces before the dissolution test with the same
sieve, which was used for the ES sample. The composition and the applied
abbreviation of the film cast sample can be found in . Finally, electrospraying
was performed to investigate the effect
of the electrostatic field on the quality of the product. Because
we planned to achieve a similar round-shaped morphology as in the
case of spray drying, the same composition was used . The abovementioned multifunctional
apparatus was used for the preparation of electrosprayed (ESY) samples.
The adjusted process parameters were similar to those applied for
spray drying. The only difference was the utilization of 40 kV voltage
on the atomizer. 2.3 X-ray Powder Diffraction
(XRPD) One
of the applied methods for the investigation of the amorphous characteristics
of the samples was X-ray powder diffraction. The measurements were
performed with a PANalytical X’pert Pro MPD X-ray diffractometer
(Almelo, The Netherlands) using Cu Kα radiation (1.506 Å)
and a Ni filter. The applied current was 30 mA, while the voltage
was 40 kV. The adjusted scan range was between 2θ angles of
4 and 44°. 2.4 Differential Scanning Calorimetry
(DSC) The amorphous characteristic of the prepared samples
was also examined
by DSC. The thermograms were recorded using a Setaram DSC 92 (Caluire,
France). Nitrogen flush was introduced into the chamber with a continuous
flow of 50 mL/min. The applied temperature program started with an
isothermal part of 1 min at ambient temperature, which was followed
by linear heating from 25 to 250 °C at a rate of 10 °C/min. 2.5 Thermogravimetric Analysis (TGA) and Mass
Loss Measurement Thermogravimetric analysis of the samples
was performed by a Q5000 TGA instrument (TA Instruments). The ES fibers
and spray-dried (SD) powder (ca. 10 mg) were heated from 25 to 250
°C at 10 °C/min using a 25 mL/min nitrogen flush. Solvent evaporation was investigated by a simple mass loss analysis,
where the mass of the products was measured over time under atmospheric
circumstances (no inert gas was applied). The samples were placed
on an analytical balance (Sartorius AC 210 and SQP-F, Göttingen,
Germany) at 25 °C for 90 min immediately after preparation. A
computer using data processing software (written by the authors) recorded
the measured weights. 2.6 Scanning Electron Microscopy
(SEM) The morphology and size of the prepared samples were
investigated
by a JEOL JSM 6380LA (JEOL, Tokyo, Japan) type scanning electron microscope.
The specimens were fixed with conductive double-sided carbon adhesive
tape. The samples were sputtered with gold before the measurements
to avoid electrostatic charging. The SEM examinations were performed
in a high vacuum while the applied accelerating voltage and the working
distance were 10 kV and between 10 and 15 mm, respectively. A randomized
diameter determination method was used to calculate the average diameter
of the SD particles and the fibers. 2.7 In Vitro Dissolution Testing Dissolution
of the SPIR-loaded samples was measured with a Pharma Test PTWS 600
dissolution tester (Pharma Test Apparatebau AG, Hainburg, Germany),
which was coupled with an Agilent 8453 ultraviolet–visible
(UV–vis) spectrophotometer (Agilent Technologies, Santa Clara,
CA) for online determination of the dissolved API through a flow cell
system. The current concentration of the dissolved SPIR was calculated
in real-time based on a preliminarily built calibration at a wavelength
of 243 nm. All of the samples were investigated by the so-called “tapped
basket” dissolution method, which is a mixture of the basket
(USP I) and the paddle (USP II) apparatus. The ES product was pushed through a sieve before the dissolution
test. The stirrer speed was set to 50 rpm, and 900 mL of 0.1 N HCl
dissolution media at a temperature of (37 ± 0.5) °C was
applied during the measurements. The API content was 50 mg in all
dissolution tests, and each sample was examined in triplicate. 2.8 Laser Diffraction The particle size
distribution of the ground ES, the SD, and the crushed film-cast (FC)
samples were determined by a Malvern Mastersizer 2000 type laser diffractometer
(Malvern Instruments Ltd., Worchestershire, U.K.). The background
recording took 45 s while the measurement time was set to 1 min. The
intensity of the vibrational sample feeder was adjusted to 75%. The
applied pressure was 1.5 bar during all measurements. The volume equivalent
sphere diameter was used to characterize the particle size. The measured d (0.5) values described the 50% cumulative undersize
of the volumetric distribution. 2.9 Polarized
Light Optical Microscopy An Amplival Carl Zeiss (Jena, Germany)
polarized microscope with
an OLYMPUS C4040 Z type camera was used for the detection of crystalline
traces in the prepared samples. The agglomerates of the prepared samples
were separated to individual particles with silicon oil during sample
preparation. The collection and evaluation of the images were implemented
with DP-Soft software. 2.10 Raman Spectroscopy and
Mapping The
temperature-induced decomposition of the samples, the effect of the
dissolution media on the samples, and the possible crystalline traces
in the prepared ASDs were examined with a Horiba Jobin Yvon LabRAM
system coupled with an external 785 nm diode laser source and an Olympus
BX-40 optical microscope. To increase the confocal performance and
reduce the analysis volume, a confocal hole of 500 μm, half
of the maximum diameter, was used in the confocal system. In addition,
a 950 groove/mm grating monochromator was used to disperse the Raman
photons before they reach the CCD detector. An objective of
20× magnification (laser spot size: ∼3 μm) was applied
during the investigation of temperature-induced decomposition and
the impact of the dissolution media. The spectrograph position was
set to 1200 cm –1 to measure the spectral range of
570–1765 cm –1 with 4 cm –1 resolution. The applied acquisition time was adjusted to 60 s with
2-time accumulation. To examine the temperature-induced decomposition,
the temperature of the ES and SD samples were controlled by a Linkam
THMS600 heating/cooling stage (Linkam, United Kingdom). The adjusted
temperature program comprised linear heating from 25 to 250 °C
with a 10 °C/min heating rate. To measure the impact of the HCl
solution, pastilles were formed from 100 mg of SD powder and 100 mg
of the ES sample, and then 20 μL of the dissolution medium was
dropped onto the surface of each pastille. The flat round pastilles
were prepared with a Camilla OL95 type press using 50 bar pressure.
The thickness and diameter of the pastilles were ∼1.5 and 12
mm, respectively. Investigation of the crystalline traces in
the pure ES and SD samples
was performed by Raman mapping, where pastilles of the ASDs were examined.
A 50× objective (laser spot size: ∼2 μm) was used
for this purpose. The spectral range was the same as in the case of
simple spectrum collection. The maps were recorded with a 5 μm
step size in both directions and contained 41 × 41 points. Every
single spectrum acquisition took 20 s, and two spectra were averaged
at each measured point. The evaluation of the Raman mapping was conducted
using the classical least-squares (CLS) method in LabSpec 5.41 (Horiba
Jobin Yvon S.A.S., Villeneuve d’Ascq, France). Spectra of crystalline
SPIR, amorphous SPIR, and PVPVA64 were applied as references during
chemometric analysis. 2.11 Borescope An
Olympus A50372A borescope
was utilized to investigate the precipitation in the dissolution media.
The outer diameter was 5 mm, while the direction of the view was 0°. 

Materials Micronized SPIR (Form II)
( a) (melting
point: 211 °C) was received from Gedeon Richter Plc. (Budapest,
Hungary). PVPVA64 (Kollidon VA64) ( b) was kindly provided by BASF (Ludwigshafen,
Germany). Dichloromethane (DCM) and absolute ethanol (EtOH) were analytical
grade, and both were purchased from Merck Ltd. (Budapest, Hungary)
and used without any further purification. For the dissolution tests,
37 w/w % HCl was ordered from Merck Ltd. (Budapest, Hungary). 

Sample Preparation A multifunctional
apparatus was used to prepare SPIR-loaded ASDs  to reduce technological differences. , The equipment was originally developed for electrospinning, but
it can be perfectly operated as a rotary spray dryer. The key element
of the machine is a round-shaped, stainless steel spinneret with orifices
( d spinneret = 34 mm, d orifice = 330 μm), connected to a high-speed motor.
The rotational speed of the spinneret was set to 40 000 rpm
during both experiments. ASDs were prepared at ambient temperature
(25 °C) and 45 ± 5% relative humidity. A grounded stainless
steel cone at the bottom of the drying chamber was used. The products
were periodically removed from the grounded metal cone with automated
air knives (pressurized blowing air) and were collected in a cyclone,
which enabled the application of the system in continuous manufacturing
mode. A previously determined drug–polymer ratio was used for
electrospinning with 40% SPIR and 60% PVPVA64. The solvent mixture consisted of dichloromethane and ethanol,
which were already tested for high-speed electrospinning of itraconazole. During spray drying, a less viscous solution
was used than that in the case of electrospinning experiments. summarizes the exact
amount of raw materials used and the sample codes. The solutions were
fed into the spinneret with a Watson–Marlow peristaltic pump
(Watson–Marlow Fluid Technology Group, Budapest, Hungary).
The applied feeding rates were 300 and 600 mL/h in the case of the
electrospinning and spray drying, respectively. For fiber formation,
40 kV positive, a direct current voltage was applied to the grounded
stainless steel spinneret during electrospinning. The electrospun
(ES) product was pushed through a sieve with a hole size of 0.8 mm
after the preparation to achieve a more uniform macroscopic particle
size. The influence of the drying kinetics was also
examined through
the preparation of samples by film casting. The solution of SPIR and
PVPVA64 was cast into square-shaped silicon molds (3 × 50 ×
50 mm 3 ) and dried for 3 days at room temperature. The thickness
of the film was 70 ± 5 μm, which was determined with a
Pro-Max Electronic Digital Caliper (NSK, Tokyo, Japan). The film was
ground into small pieces before the dissolution test with the same
sieve, which was used for the ES sample. The composition and the applied
abbreviation of the film cast sample can be found in . Finally, electrospraying
was performed to investigate the effect
of the electrostatic field on the quality of the product. Because
we planned to achieve a similar round-shaped morphology as in the
case of spray drying, the same composition was used . The abovementioned multifunctional
apparatus was used for the preparation of electrosprayed (ESY) samples.
The adjusted process parameters were similar to those applied for
spray drying. The only difference was the utilization of 40 kV voltage
on the atomizer. 

X-ray Powder Diffraction
(XRPD) One
of the applied methods for the investigation of the amorphous characteristics
of the samples was X-ray powder diffraction. The measurements were
performed with a PANalytical X’pert Pro MPD X-ray diffractometer
(Almelo, The Netherlands) using Cu Kα radiation (1.506 Å)
and a Ni filter. The applied current was 30 mA, while the voltage
was 40 kV. The adjusted scan range was between 2θ angles of
4 and 44°. 

Differential Scanning Calorimetry
(DSC) The amorphous characteristic of the prepared samples
was also examined
by DSC. The thermograms were recorded using a Setaram DSC 92 (Caluire,
France). Nitrogen flush was introduced into the chamber with a continuous
flow of 50 mL/min. The applied temperature program started with an
isothermal part of 1 min at ambient temperature, which was followed
by linear heating from 25 to 250 °C at a rate of 10 °C/min. 

Thermogravimetric Analysis (TGA) and Mass
Loss Measurement Thermogravimetric analysis of the samples
was performed by a Q5000 TGA instrument (TA Instruments). The ES fibers
and spray-dried (SD) powder (ca. 10 mg) were heated from 25 to 250
°C at 10 °C/min using a 25 mL/min nitrogen flush. Solvent evaporation was investigated by a simple mass loss analysis,
where the mass of the products was measured over time under atmospheric
circumstances (no inert gas was applied). The samples were placed
on an analytical balance (Sartorius AC 210 and SQP-F, Göttingen,
Germany) at 25 °C for 90 min immediately after preparation. A
computer using data processing software (written by the authors) recorded
the measured weights. 

Scanning Electron Microscopy
(SEM) The morphology and size of the prepared samples were
investigated
by a JEOL JSM 6380LA (JEOL, Tokyo, Japan) type scanning electron microscope.
The specimens were fixed with conductive double-sided carbon adhesive
tape. The samples were sputtered with gold before the measurements
to avoid electrostatic charging. The SEM examinations were performed
in a high vacuum while the applied accelerating voltage and the working
distance were 10 kV and between 10 and 15 mm, respectively. A randomized
diameter determination method was used to calculate the average diameter
of the SD particles and the fibers. 

In Vitro Dissolution Testing Dissolution
of the SPIR-loaded samples was measured with a Pharma Test PTWS 600
dissolution tester (Pharma Test Apparatebau AG, Hainburg, Germany),
which was coupled with an Agilent 8453 ultraviolet–visible
(UV–vis) spectrophotometer (Agilent Technologies, Santa Clara,
CA) for online determination of the dissolved API through a flow cell
system. The current concentration of the dissolved SPIR was calculated
in real-time based on a preliminarily built calibration at a wavelength
of 243 nm. All of the samples were investigated by the so-called “tapped
basket” dissolution method, which is a mixture of the basket
(USP I) and the paddle (USP II) apparatus. The ES product was pushed through a sieve before the dissolution
test. The stirrer speed was set to 50 rpm, and 900 mL of 0.1 N HCl
dissolution media at a temperature of (37 ± 0.5) °C was
applied during the measurements. The API content was 50 mg in all
dissolution tests, and each sample was examined in triplicate. 

Laser Diffraction The particle size
distribution of the ground ES, the SD, and the crushed film-cast (FC)
samples were determined by a Malvern Mastersizer 2000 type laser diffractometer
(Malvern Instruments Ltd., Worchestershire, U.K.). The background
recording took 45 s while the measurement time was set to 1 min. The
intensity of the vibrational sample feeder was adjusted to 75%. The
applied pressure was 1.5 bar during all measurements. The volume equivalent
sphere diameter was used to characterize the particle size. The measured d (0.5) values described the 50% cumulative undersize
of the volumetric distribution. 

Polarized
Light Optical Microscopy An Amplival Carl Zeiss (Jena, Germany)
polarized microscope with
an OLYMPUS C4040 Z type camera was used for the detection of crystalline
traces in the prepared samples. The agglomerates of the prepared samples
were separated to individual particles with silicon oil during sample
preparation. The collection and evaluation of the images were implemented
with DP-Soft software. 

Raman Spectroscopy and
Mapping The
temperature-induced decomposition of the samples, the effect of the
dissolution media on the samples, and the possible crystalline traces
in the prepared ASDs were examined with a Horiba Jobin Yvon LabRAM
system coupled with an external 785 nm diode laser source and an Olympus
BX-40 optical microscope. To increase the confocal performance and
reduce the analysis volume, a confocal hole of 500 μm, half
of the maximum diameter, was used in the confocal system. In addition,
a 950 groove/mm grating monochromator was used to disperse the Raman
photons before they reach the CCD detector. An objective of
20× magnification (laser spot size: ∼3 μm) was applied
during the investigation of temperature-induced decomposition and
the impact of the dissolution media. The spectrograph position was
set to 1200 cm –1 to measure the spectral range of
570–1765 cm –1 with 4 cm –1 resolution. The applied acquisition time was adjusted to 60 s with
2-time accumulation. To examine the temperature-induced decomposition,
the temperature of the ES and SD samples were controlled by a Linkam
THMS600 heating/cooling stage (Linkam, United Kingdom). The adjusted
temperature program comprised linear heating from 25 to 250 °C
with a 10 °C/min heating rate. To measure the impact of the HCl
solution, pastilles were formed from 100 mg of SD powder and 100 mg
of the ES sample, and then 20 μL of the dissolution medium was
dropped onto the surface of each pastille. The flat round pastilles
were prepared with a Camilla OL95 type press using 50 bar pressure.
The thickness and diameter of the pastilles were ∼1.5 and 12
mm, respectively. Investigation of the crystalline traces in
the pure ES and SD samples
was performed by Raman mapping, where pastilles of the ASDs were examined.
A 50× objective (laser spot size: ∼2 μm) was used
for this purpose. The spectral range was the same as in the case of
simple spectrum collection. The maps were recorded with a 5 μm
step size in both directions and contained 41 × 41 points. Every
single spectrum acquisition took 20 s, and two spectra were averaged
at each measured point. The evaluation of the Raman mapping was conducted
using the classical least-squares (CLS) method in LabSpec 5.41 (Horiba
Jobin Yvon S.A.S., Villeneuve d’Ascq, France). Spectra of crystalline
SPIR, amorphous SPIR, and PVPVA64 were applied as references during
chemometric analysis. 

Borescope An
Olympus A50372A borescope
was utilized to investigate the precipitation in the dissolution media.
The outer diameter was 5 mm, while the direction of the view was 0°. 

Results and Discussion The main goal of this
work was to compare two different solvent-based
ASD preparation methods with similar productivity. The effect of the
differences in the production circumstances and drying kinetics on
the product properties, such as morphology, amorphous characteristics,
and dissolution, were investigated. Our aim was to prepare good quality
products and make the methods comparable as much as possible. For
this reason, the same apparatus with the same collection method, the
same solid production rate, the same drying temperature, the same
spinneret, and the same rotational speed of the spinneret was used.
Overall, there were only three differences between the two methods:
the solution concentrations, the adjusted feeding rate of the solutions,
and the application of high voltage during electrospinning. 3.1 Preparation of the ES and SD Samples For preparing
SPIR-loaded fibers with a small fiber diameter, the
feeding rate during the electrospinning experiment was set based on
our previous studies. According to the SEM images, fibrous samples
were produced successfully with an average fiber diameter of 1.27
± 0.59 μm ( a). The fibrous structure was retained even after grinding;
therefore, the prepared ASD was found to be suitable for further downstream
processing such as blending and tableting ( b). The particle size analysis of the ground
ES samples based on laser diffraction showed multimodal distribution
with a d (0.5) = 10.533 μm . Multiple peaks
were explained by the difference in the size of the agglomerates,
which were formed after grinding. A yield
of 70% was obtained during fiber preparation, and corresponded to
∼70 g/h productivity. This value was much higher than the ∼0.01
to 1 g/h productivities, which were achieved by the basic electrospinning
setups. In addition, it was possible
to enhance the output by increasing the number of spinnerets. The next step was to achieve similar productivity with spray drying.
Twice as much solvent was used to obtain uniform particles with satisfactory
efficiency. To achieve ∼70 g/h productivity from the lower
viscosity solution, a 600 mL/h feeding rate was needed. Since the
concentration was half of that used during electrospinning, the doubled
feeding rate resulted in the same solid material production in the
case of spray drying. A rotary atomizer allowed quick solvent evaporation,
thanks to the high shear forces, the applied feeding rate was appropriate
to make round-shaped SD particles with an average diameter of 13.13
± 6.25 μm according to the SEM images, and with d (0.5) = 10.766 μm based on the laser diffraction
measurement ( c and ). The achieved ∼70% yield
value of both the methods is satisfactory
during the short periods examined as the efficiency may be enhanced
with a longer, continuous production process. The main reason for
the material losses is that the samples were stuck to the wall of
the drying chamber. However, the application of air knives during
the process can further increase the yield of the two solvent-based
ASD preparation methods. Nonetheless, the equipment used works continuously;
therefore, the total productivity could be increased. 3.2 DSC and XRPD Measurements Examination
of the physical state of SPIR in the ES and SD samples was accomplished
by DSC and XRPD after drying them for 3 days at room temperature.
Pure crystalline SPIR and PVPVA64 were measured as references. The
sharp, endothermic melting peak of the crystalline SPIR at 211 °C
did not appear in the thermograms of the ES and SD samples, which
indicated the amorphous character of the prepared materials ( a). The wide endothermic
sign at the beginning of the thermograms of the ASDs can be explained
by the water loss of the polymer. Thermogravimetric analysis of the
ES and SD samples did not show any significant difference after 3
days of drying at room temperature, and the weight losses were less
than that of the pure polymer, which indicated that the ASDs were
free of residual solvents after 3 days ( b). The decomposition of SPIR to canrenone
was observed in the thermograms at 223 and 227 °C in the ES and
the SD samples, respectively. To differentiate these peaks from the
melting peak of the crystalline SPIR, thermogravimetric analysis was
performed where the weight loss at the given temperatures showed the
decomposition of the API. Furthermore,
the characteristic Raman peaks of canrenone (a metabolite of spironolactone)
were detectable by Raman spectroscopy, which also proved the decomposition
of the API ( c). XRPD results proved the success
of amorphization as well because the sharp peaks of the crystalline
SPIR did not appear on the diffractograms of the ES and SD samples
( d). 3.3 Dissolution Tests The dissolution
results showed a fast release of SPIR from both ASD formulations,
which can satisfy the requirements of immediate-release drug products
. In addition,
standard deviations of the repeated measurements proved to be negligible
thus, it can be stated that a high macroscopic homogeneity of the
powders was reached. However, a lower dissolution extent was observed
during the measurements of SD samples. After an initial rapid increase
in the dissolution, a plateau was achieved in the first 10 min since
very quick precipitation took place in the case of the SD material.
The ES fibers dissolved nearly 100%, while the maximal dissolution
of the SD particles reached only the value of the micronized crystalline
SPIR, which suggested that the SD material recrystallized in the dissolution
media. A comparison of the dissolution media of the ES and SD materials
highlighted that the precipitation of the API from the SD particles
was clearly visible . The opaque solution indicates that SPIR was in a supersaturated
state, and no more API could dissolve in the dissolution media. The
dissolution of the prepared ASDs was investigated with a borescope
as well. The probe in pure dissolution media showed a black background.
At the beginning of the test, the ES fibers dispersed in the dissolution
media while the SD particles precipitated almost immediately. Both
effects could be tracked with the probe, which showed turbid solutions
in the first minute. After 120 min, the ES fibers dissolved completely
in 0.1 M HCl medium, and the image of the probe showed the black background
again. The precipitation of the SD samples was observed even at the
end of the dissolution tests, where the recordings of the probe indicated
the precipitated particles. Based on the results, the applied borescope
is a promising tool to monitor the effect of supersaturation and predict
the dissolution of quick precipitation systems. For a better understanding of the dissolution process, Raman
spectroscopy
was used to monitor the precipitation caused by the dissolution media
. A small
volume of the HCl medium was dropped onto the surface of the ES and
SD pastilles to imitate and examine the processes that occur during
the dissolution. The Raman spectra of the starting materials show
band-broadening, which suggests that SPIR was in the amorphous form
within the ASDs. However, narrow peaks
appeared in the spectra of SD pastilles after coming in contact with
the dissolution media. The most characteristic peak of crystalline
SPIR can be seen at 1690 cm –1 ; therefore, it can
be stated that the dissolution media induced quick crystallization
of the amorphous SD samples. 3.4 Micro-Morphological Background
of Quick Precipitation
of SD Samples According to the DSC, XRPD, and Raman spectroscopy
results, the ES and SD samples were amorphous before the dissolution
test, and no significant differences were observed between these materials.
Based on the measurements, the difference in the dissolution properties
of the ASD samples cannot be explained. Although the dissolution tests
of the two samples showed remarkable differences, an in-depth investigation
of the ES fibers and the SD particles was needed. The polarized
light microscopy images did not show birefringence in the ES samples
( a), while
some little green and purple spots were visible in the SD material,
which indicated traces of crystallites ( b). Birefringence was visible almost on every
single particle. Although the amount of crystallized samples just
reached the limit of detection of polarized light microscopy, the
dissolution of SD powder deteriorated significantly. Consequently,
crystalline SPIR should be detected using more sensitive analytical
methods. To measure the exact amount of crystalline traces, Raman microscopy
mapping was carried out . This analytical tool proved to be appropriate for
detecting small quantities of crystalline SPIR with local analysis.
In addition, CLS modeling made it possible to determine the crystalline
percentage of the samples using crystalline and amorphous SPIR as
references. As expected, the SD powder contained plenty of local crystalline
traces ( b),
while no noticeable crystallinity was observed in the case of the
fibrous samples ( a). The local quantity of crystalline SPIR at the investigated
points reached 5–7% in the SD material. This value was below
1% in the ES samples, which is comparable with the model error of
CLS. The existing crystalline nuclei in the SD particles (and the
related arrangement of the surrounding randomly arranged molecules)
allowed rapid crystallization under the dissolution circumstances
and the presence of the solvent accelerated the molecular movement
leading to crystal growth. The Raman mapping gave a good explanation
for the better dissolution properties of the fibrous material. These
results correlated well with our previous results where the relationship
between the crystalline traces and dissolution was investigated. From the polarized microscopic
images and the Raman mapping, it
can be deduced that the molecular dispersity of the API was not perfect
in the SD samples. This unequal molecular
dispersity in the ASD led to the formation of crystalline traces,
which induced precipitation during dissolution. 3.5 Investigation of the Possible Reasons for
the Formation of Crystalline Traces The dissolution results
of the ES and SD samples made clear that the differences in the ASD
preparation methods have a huge impact on the physical properties
of the generally amorphous product. Consequently, the prepared ASD
samples reacted differently in the dissolution media, which was due
to the presence of crystalline traces in the SD particles. To explore
the origin of the micro-morphological difference, a more detailed
analysis was performed. The solvent evaporation rate can be
a possible factor influencing the formation of crystalline traces.
Since the drying kinetics during ASD preparation is difficult to determine,
the weight loss of the samples at 25 °C was measured right after
its preparation. The weight-loss rates of residual solvents in the
first 20 min were 0.125 and 0.09 w/w %/min in the case of the ES and
SD samples, respectively. It can be stated that the higher specific
surface area of ES fibers facilitates solvent evaporation after ASD
preparation, which may be similar during solid particle formation.
Slower solvent evaporation can result in supersaturated areas for
a longer time during the preparation of ASDs, where the API molecules
can arrange to form a crystalline structure. The influence of
the evaporation rate on the dissolution was also
examined by the preparation of the film-cast (FC) sample . Because solvent
evaporation during film casting is relatively slow, the effect of
the drying kinetic can be investigated well. The polarized microscopic images of the FC product showed birefringence,
which refers to the crystallinity of the sample. The dissolution profile
of the FC sample confirmed the formation of crystalline traces because
the lower evaporation rate of the residual solvents results in the
deterioration of dissolution properties. The lower dissolution of
the FC sample compared to the crystalline SPIR may be explained by
the larger particle size  and crystallinity of the films. Besides the evaporation rate of
solvents, the electrostatic field
might have an influence on particle formation and the drying kinetic
during the ASD preparation methods. To identify the effect of the
electrostatic forces on the product quality and thus on the dissolution,
electrospraying was performed. The application of this electrostatic
force-based method resulted in round-shaped particles instead of fibrous
structures due to the half concentration of the feed solution. The
morphology of the ESY sample showed similarity to the SD particles
while the average diameter of the ESY particles was 6.48 ± 3.89
μm according to the SEM images, which is approximately half
that of the SD samples ( d = 13.13 ± 6.25 μm).
The dissolution of the ESY particles proved to be better compared
to the SD sample . The results assumed that the formation of local crystalline
traces was avoidable in the presence of an electrostatic field since
dissolution reached almost the level of the ES fibers. The explanation
of these results can be that Coulomb fission during the electrostatic
force-based methods affects the evaporation rate and contributes to
the orientation of the API molecules in the ASDs. − Further investigation
of electrospraying might be needed for a deeper understanding of the
effect of the electrostatic field on particle formation. 

Preparation of the ES and SD Samples For preparing
SPIR-loaded fibers with a small fiber diameter, the
feeding rate during the electrospinning experiment was set based on
our previous studies. According to the SEM images, fibrous samples
were produced successfully with an average fiber diameter of 1.27
± 0.59 μm ( a). The fibrous structure was retained even after grinding;
therefore, the prepared ASD was found to be suitable for further downstream
processing such as blending and tableting ( b). The particle size analysis of the ground
ES samples based on laser diffraction showed multimodal distribution
with a d (0.5) = 10.533 μm . Multiple peaks
were explained by the difference in the size of the agglomerates,
which were formed after grinding. A yield
of 70% was obtained during fiber preparation, and corresponded to
∼70 g/h productivity. This value was much higher than the ∼0.01
to 1 g/h productivities, which were achieved by the basic electrospinning
setups. In addition, it was possible
to enhance the output by increasing the number of spinnerets. The next step was to achieve similar productivity with spray drying.
Twice as much solvent was used to obtain uniform particles with satisfactory
efficiency. To achieve ∼70 g/h productivity from the lower
viscosity solution, a 600 mL/h feeding rate was needed. Since the
concentration was half of that used during electrospinning, the doubled
feeding rate resulted in the same solid material production in the
case of spray drying. A rotary atomizer allowed quick solvent evaporation,
thanks to the high shear forces, the applied feeding rate was appropriate
to make round-shaped SD particles with an average diameter of 13.13
± 6.25 μm according to the SEM images, and with d (0.5) = 10.766 μm based on the laser diffraction
measurement ( c and ). The achieved ∼70% yield
value of both the methods is satisfactory
during the short periods examined as the efficiency may be enhanced
with a longer, continuous production process. The main reason for
the material losses is that the samples were stuck to the wall of
the drying chamber. However, the application of air knives during
the process can further increase the yield of the two solvent-based
ASD preparation methods. Nonetheless, the equipment used works continuously;
therefore, the total productivity could be increased. 

DSC and XRPD Measurements Examination
of the physical state of SPIR in the ES and SD samples was accomplished
by DSC and XRPD after drying them for 3 days at room temperature.
Pure crystalline SPIR and PVPVA64 were measured as references. The
sharp, endothermic melting peak of the crystalline SPIR at 211 °C
did not appear in the thermograms of the ES and SD samples, which
indicated the amorphous character of the prepared materials ( a). The wide endothermic
sign at the beginning of the thermograms of the ASDs can be explained
by the water loss of the polymer. Thermogravimetric analysis of the
ES and SD samples did not show any significant difference after 3
days of drying at room temperature, and the weight losses were less
than that of the pure polymer, which indicated that the ASDs were
free of residual solvents after 3 days ( b). The decomposition of SPIR to canrenone
was observed in the thermograms at 223 and 227 °C in the ES and
the SD samples, respectively. To differentiate these peaks from the
melting peak of the crystalline SPIR, thermogravimetric analysis was
performed where the weight loss at the given temperatures showed the
decomposition of the API. Furthermore,
the characteristic Raman peaks of canrenone (a metabolite of spironolactone)
were detectable by Raman spectroscopy, which also proved the decomposition
of the API ( c). XRPD results proved the success
of amorphization as well because the sharp peaks of the crystalline
SPIR did not appear on the diffractograms of the ES and SD samples
( d). 

Dissolution Tests The dissolution
results showed a fast release of SPIR from both ASD formulations,
which can satisfy the requirements of immediate-release drug products
. In addition,
standard deviations of the repeated measurements proved to be negligible
thus, it can be stated that a high macroscopic homogeneity of the
powders was reached. However, a lower dissolution extent was observed
during the measurements of SD samples. After an initial rapid increase
in the dissolution, a plateau was achieved in the first 10 min since
very quick precipitation took place in the case of the SD material.
The ES fibers dissolved nearly 100%, while the maximal dissolution
of the SD particles reached only the value of the micronized crystalline
SPIR, which suggested that the SD material recrystallized in the dissolution
media. A comparison of the dissolution media of the ES and SD materials
highlighted that the precipitation of the API from the SD particles
was clearly visible . The opaque solution indicates that SPIR was in a supersaturated
state, and no more API could dissolve in the dissolution media. The
dissolution of the prepared ASDs was investigated with a borescope
as well. The probe in pure dissolution media showed a black background.
At the beginning of the test, the ES fibers dispersed in the dissolution
media while the SD particles precipitated almost immediately. Both
effects could be tracked with the probe, which showed turbid solutions
in the first minute. After 120 min, the ES fibers dissolved completely
in 0.1 M HCl medium, and the image of the probe showed the black background
again. The precipitation of the SD samples was observed even at the
end of the dissolution tests, where the recordings of the probe indicated
the precipitated particles. Based on the results, the applied borescope
is a promising tool to monitor the effect of supersaturation and predict
the dissolution of quick precipitation systems. For a better understanding of the dissolution process, Raman
spectroscopy
was used to monitor the precipitation caused by the dissolution media
. A small
volume of the HCl medium was dropped onto the surface of the ES and
SD pastilles to imitate and examine the processes that occur during
the dissolution. The Raman spectra of the starting materials show
band-broadening, which suggests that SPIR was in the amorphous form
within the ASDs. However, narrow peaks
appeared in the spectra of SD pastilles after coming in contact with
the dissolution media. The most characteristic peak of crystalline
SPIR can be seen at 1690 cm –1 ; therefore, it can
be stated that the dissolution media induced quick crystallization
of the amorphous SD samples. 

Micro-Morphological Background
of Quick Precipitation
of SD Samples According to the DSC, XRPD, and Raman spectroscopy
results, the ES and SD samples were amorphous before the dissolution
test, and no significant differences were observed between these materials.
Based on the measurements, the difference in the dissolution properties
of the ASD samples cannot be explained. Although the dissolution tests
of the two samples showed remarkable differences, an in-depth investigation
of the ES fibers and the SD particles was needed. The polarized
light microscopy images did not show birefringence in the ES samples
( a), while
some little green and purple spots were visible in the SD material,
which indicated traces of crystallites ( b). Birefringence was visible almost on every
single particle. Although the amount of crystallized samples just
reached the limit of detection of polarized light microscopy, the
dissolution of SD powder deteriorated significantly. Consequently,
crystalline SPIR should be detected using more sensitive analytical
methods. To measure the exact amount of crystalline traces, Raman microscopy
mapping was carried out . This analytical tool proved to be appropriate for
detecting small quantities of crystalline SPIR with local analysis.
In addition, CLS modeling made it possible to determine the crystalline
percentage of the samples using crystalline and amorphous SPIR as
references. As expected, the SD powder contained plenty of local crystalline
traces ( b),
while no noticeable crystallinity was observed in the case of the
fibrous samples ( a). The local quantity of crystalline SPIR at the investigated
points reached 5–7% in the SD material. This value was below
1% in the ES samples, which is comparable with the model error of
CLS. The existing crystalline nuclei in the SD particles (and the
related arrangement of the surrounding randomly arranged molecules)
allowed rapid crystallization under the dissolution circumstances
and the presence of the solvent accelerated the molecular movement
leading to crystal growth. The Raman mapping gave a good explanation
for the better dissolution properties of the fibrous material. These
results correlated well with our previous results where the relationship
between the crystalline traces and dissolution was investigated. From the polarized microscopic
images and the Raman mapping, it
can be deduced that the molecular dispersity of the API was not perfect
in the SD samples. This unequal molecular
dispersity in the ASD led to the formation of crystalline traces,
which induced precipitation during dissolution. 

Investigation of the Possible Reasons for
the Formation of Crystalline Traces The dissolution results
of the ES and SD samples made clear that the differences in the ASD
preparation methods have a huge impact on the physical properties
of the generally amorphous product. Consequently, the prepared ASD
samples reacted differently in the dissolution media, which was due
to the presence of crystalline traces in the SD particles. To explore
the origin of the micro-morphological difference, a more detailed
analysis was performed. The solvent evaporation rate can be
a possible factor influencing the formation of crystalline traces.
Since the drying kinetics during ASD preparation is difficult to determine,
the weight loss of the samples at 25 °C was measured right after
its preparation. The weight-loss rates of residual solvents in the
first 20 min were 0.125 and 0.09 w/w %/min in the case of the ES and
SD samples, respectively. It can be stated that the higher specific
surface area of ES fibers facilitates solvent evaporation after ASD
preparation, which may be similar during solid particle formation.
Slower solvent evaporation can result in supersaturated areas for
a longer time during the preparation of ASDs, where the API molecules
can arrange to form a crystalline structure. The influence of
the evaporation rate on the dissolution was also
examined by the preparation of the film-cast (FC) sample . Because solvent
evaporation during film casting is relatively slow, the effect of
the drying kinetic can be investigated well. The polarized microscopic images of the FC product showed birefringence,
which refers to the crystallinity of the sample. The dissolution profile
of the FC sample confirmed the formation of crystalline traces because
the lower evaporation rate of the residual solvents results in the
deterioration of dissolution properties. The lower dissolution of
the FC sample compared to the crystalline SPIR may be explained by
the larger particle size  and crystallinity of the films. Besides the evaporation rate of
solvents, the electrostatic field
might have an influence on particle formation and the drying kinetic
during the ASD preparation methods. To identify the effect of the
electrostatic forces on the product quality and thus on the dissolution,
electrospraying was performed. The application of this electrostatic
force-based method resulted in round-shaped particles instead of fibrous
structures due to the half concentration of the feed solution. The
morphology of the ESY sample showed similarity to the SD particles
while the average diameter of the ESY particles was 6.48 ± 3.89
μm according to the SEM images, which is approximately half
that of the SD samples ( d = 13.13 ± 6.25 μm).
The dissolution of the ESY particles proved to be better compared
to the SD sample . The results assumed that the formation of local crystalline
traces was avoidable in the presence of an electrostatic field since
dissolution reached almost the level of the ES fibers. The explanation
of these results can be that Coulomb fission during the electrostatic
force-based methods affects the evaporation rate and contributes to
the orientation of the API molecules in the ASDs. − Further investigation
of electrospraying might be needed for a deeper understanding of the
effect of the electrostatic field on particle formation. 

Conclusions Multifunctional equipment was successfully
applied to prepare ES
fibers and SD particles in a continuous way with similar productivity.
Both produced samples proved to be amorphous according to the DSC
and XRPD results. The increased specific surface area and the amorphous
forms facilitated the dissolution, and thus immediate drug release
was realized. However, the dissolution extent enhanced only for the
ES product while the SD sample showed a similar final release of crystalline
SPIR. In further experiments, the origin of the deterioration of dissolution
properties was examined. Traces of crystallinity in the SD particles
was detected by polarized microscopy and Raman mapping. The latter
was able to determine the local amounts (5–7%) of the crystalline
impurity in the SD sample using CLS modeling, which provides the explanation
for the precipitation of SD particles during dissolution. According
to the findings of this research, electrospinning seemed to be more
effective in the context of amorphization of the investigated API-polymer
composition. A simple mass loss analysis of ES and SD products showed
that the faster solvent evaporation rate during the electrospinning
can be a possible reason for the preparation of a more stable amorphous
system, which retains its advantageous properties even during the
dissolution tests. Furthermore, the preparation of FC and ESY samples
revealed that the size and shape of the products, and the electrostatic
forces might influence the efficiency of the amorphization in the
case of the presented SPIR-PVPVA64 composition. It is important
to note that the evaporation rate of solvents can
vary over a wide range during spray drying, which results in either
hardly detectable or even easily measurable crystallinity in the product. Consequently, the dissolution of the SD samples
depends largely on the process parameter of the preparation method. , In contrast to spray drying, electrospinning provides a more reliable
way to prepare ASDs without crystalline traces since the electrostatic
forces contribute to more effective solvent evaporation. Therefore,
the preparation method plays a particularly important role in the
case of noninteracting ASDs because no intermolecular or intramolecular
hydrogen-bonds and interactions can be formed, which could prevent
recrystallization during the dissolution or the storage if there are
crystalline impurities in the system. In conclusion, electrospinning
proved to be a promising and competitive technology with the widely
used spray drying to formulate ASDs. 

