Journal Pre-proofs

Amorphous Solid Dispersion of Ibuprofen: A Comparative Study on the Ef-

fect of Solution Based Techniques

Ahmad Ziaee, Stephen O'Dea, Aoise Howard-Hildige, Luis Padrela,

Catherine Potter, Javed Iqbal, Ahmad B. Albadarin, Gavin Walker, Emmet J.
O'Reilly

PII: S0378-5173(19)30861-0
DOI: https://doi.org/10.1016/j.ijpharm.2019.118816
Reference: IJP 118816

To appear in: International Journal of Pharmaceutics

Received Date: 8 August 2019

Revised Date: 18 October 2019
Accepted Date: 19 October 2019

Please cite this article as: A. Ziaee, S. O'Dea, A. Howard-Hildige, L. Padrela, C. Potter, J. Iqbal, A.B. Albadarin,
G. Walker, E.J. O'Reilly, Amorphous Solid Dispersion of Ibuprofen: A Comparative Study on the Effect of
Solution Based Techniques, International Journal of Pharmaceutics (2019), doi: https://doi.org/10.1016/
j.ijpharm.2019.118816

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 Amorphous Solid Dispersion of Ibuprofen: A Comparative Study on the Effect of
Solution Based Techniques

Ahmad Ziaee, Stephen O’Dea, Aoise Howard-Hildige, Luis Padrela, Catherine Potter, Javed Iqbal, Ahmad B.
Albadarin, Gavin Walker, Emmet J O’Reilly*

Synthesis & Solid State Pharmaceutical Centre (SSPC), Department of Chemical Sciences, Bernal Institute,
University of Limerick, Limerick, Ireland

1
 Abstract

Amorphous solid dispersion (ASD) is one of the most promising strategies for improving the
solubility of active pharmaceutical ingredients (APIs) with low aqueous solubility. Solvent-
based techniques such as electrospinning (ES), spray-drying (SD) and rotary evaporation
(RE), have all previously been shown to be effective techniques for formulating ASDs. To
date however, the effect of these processing techniques on the physicochemical properties
and ASD homogeneity or “quality of ASD” produced remains largely unexplored. This work
uses ibuprofen (IBU) as a model BCS class II API with two cellulosic excipients, HPMCAS
and HPMCP-HP55 to produce ASDs by employing ES, SD and RE processing techniques.
The physicochemical, morphological and dissolution properties of each sample were
evaluated and the ASD forming strengths of each of the polymers were assessed using
Differential Scanning Calorimetry (DSC). Principal |Component Analysis (PCA) of Raman
spectra of crystalline and amorphous IBU was employed for qualitative analysis of ASD
homogeneity and subsequent ASD stability during long-term storage. Results show that while
ASD formation is predominantly dependent on API:excipient ratio, the ASD homogeneity is
highly dependent on processing technique. Dissolution studies show that electrospun samples
had the highest API release rate due to their fibrous morphology and higher specific surface
area. However, these samples were the least homogenous of all ASDs produced thereby
potentially influencing sample stability during long term storage. In addition, the higher
melting point depression, higher Tg, and increased abundance of functional groups suitable
for hydrogen bonding, show HPMCAS to be a significantly better ASD co-former when
compared with HPMCP-HP55.

Keywords:

Electrospinning, Spray Drying, Rotary Evaporation, Dissolution rate, Stabilization,

Amorphous Solid Dispersion, Principal Component Analysis.

2
 1. Introduction

Enhancing the solubility of poorly water soluble drugs is currently one of the major
challenges facing the pharmaceutical industry (Albadarin et al., 2017; Baghel et al., 2016;
Kalepu and Nekkanti, 2015; Van den Mooter, 2012). Over 40 % of newly developed drugs
never reach patients due to low or reduced solubility (Takagi et al., 2006; Ziaee et al., 2017b;
Ziaee et al., 2019). According to the Biopharmaceutical Classification System (BCS), the
majority of newly developed drugs are classified as class II and exhibit low solubility despite
being highly permeable. Solubility is therefore a significant limiting factor in drug
development and the rationale for formulating advanced drug delivery systems with
improved dissolution and bioavailability profiles is clear (Lipinski et al., 2012).

Formulating amorphous solid dispersions (ASDs) is one of the most promising strategies for
improving the solubility of active pharmaceutical ingredients (APIs) with low aqueous
solubility (Leuner and Dressman, 2000; Serajuddin, 1999; Singh and Van den Mooter, 2016).
ASDs can be specifically defined as the dispersion of a drug/API, preferably at molecular
level, in an amorphous polymeric matrix (Huang and Dai, 2014) and was first introduced by
Sekiguchi and Obi in 1961 by formation of a eutectic mixture of sulphatiazole with water-
soluble excipients (Bhardwaj et al., 2018; Chen et al., 2018; G. Van den Mooter, 2012;
Sekiguchi and Obi, 1961). Since then multiple ASDs have received FDA-approval and been
introduced to the market (Ziaee et al., 2019). The choice of excipient, API/Excipient ratio and
processing technique have previously been shown to be critical factors in developing a
successful ASD formulation (Ziaee et al., 2017b). At certain API concentrations, polymeric
excipients with elevated glass transition temperatures (Tg) have been shown to enhance
antiplasticization thereby hindering nucleation and subsequent growth of crystals. The ASD
formulation processing technique has also been shown to alter the final solid-state properties
such as stability, dissolution rate and morphological appearance. Techniques including spray
drying and electrospinning have recently been investigated with a view to improving final
properties, in particular particle morphology for subsequent downstream processing (Padrela
et al., 2019; Solomon et al., 2019). Nagy et al. investigated the effect of differing processing
techniques in terms of final products dissolution rate (Nagy et al., 2015a; Nagy et al., 2013).
Final product dissolution rate is a significant consideration when formulating ASDs as in
addition to low aqueous solubility, the absorption of most poorly soluble drugs is dissolution

3
rate limited resulting in the API passing the absorption site even before complete dissolution
(Baghel et al., 2016). Therefore, a comprehensive understanding of the effect of processing
technique and physicochemical properties with respect to dissolution rate is of crucial
importance.

Spray drying (SD) is a solvent based technique in which solutions are atomized and dried
using high heat in a drying chamber and is known for high throughput and compatibility with
continuous manufacturing (Ziaee et al., 2019). SD has previously been demonstrated as an
effective technique for the preparation of ASDs (Davis et al., 2017; Patterson et al., 2007;
Ziaee et al., 2017b). In addition, techniques such as rotary evaporation (RE) (Frizon et al.,
2013; Wegiel et al., 2013) and electro-spinning/electro-spraying (ES) (Nagy et al., 2015a;
Nagy et al., 2012; Yu et al., 2010) have attracted attention from both industrial and academic
communities as potential processing techniques for new ASD formulations (Nagy et al.,
2015b; Vigha et al., 2017; Wang et al., 2017). Electrospinning/lectrospraying is a versatile,
flexible and one-step process for producing nano/micro sized particles and fibres from liquid
feedstocks and operates by utilising electric force to draw charged threads of solution onto a
grounded collector (Browne et al., 2019; Pamudji et al., 2013; Vigha et al., 2017; Yang et al.,
2016). Rotary evaporation is a relatively fast solvent evaporation technique that has been
adopted for ASD production (Bennett et al., 2015; Tominaga, 2013) however formulations
produced by this method often require further processing steps when compared those
produced by SD or ES. Z. K. Nagy et al. studied the effect of SD, film casting and ES on
formation of ASDs of itraconazole and their subsequent dissolution properties. They
observed higher dissolution rates for ES compared to SD samples which was attributed to the
higher specific surface area of the electrospun fibres (Nagy et al., 2015a).

This work focusses on examining the impact of three different solvent-based processing
techniques i.e. ES (electrospinning), SD (spray drying) and RE (rotary evaporation) on the
physiochemical and dissolution properties of ASD formulations of Ibuprofen (IBU) with the
excipients HPMCAS and HPMCP-HP55 in addition to ASD homogeneity. Ibuprofen, a BCS
class II anti-inflammatory drug was selected as a model API due to its low Tg and high
propensity to crystallise. The t50 (time taken for a 50% recrystallisation from amorphous to
crystalline) for pure IBU is in the order of minutes and as such it is a challenging API to
formulate as a stable ASD composition (Rehder et al., 2013; Wiranidchapong et al., 2015).

4
 2. Materials and methods

2.1. Materials

Hypromellose phthalate HPMCP-HP55® and hypromellose acetate succinate (also known as

hydroxypropyl methylcellulose acetate succinate) HPMCAS® were donated by Shin-Etsu
and Ashland, respectively. A racemic mixture of (RS)-ibuprofen (IBU) was purchased from
Phion Ltd. (UK). Dichloromethane (DCM) and methanol (MeOH) were both purchased from
Sigma Aldrich. Figure 1 shows the molecular structure of HPMCAS and HPMCP-HP55.
Water absorption resistance of HPMCAS and HPMCP-HP55 enhances the stability of ASDs
due to their high Tg even at high relative humidity (Huang and Dai, 2014).

(a) (b)

Figure 1; Molecular structure of excipients (a) HPMCAS, (b) HPMCP-HP55.

2.2. Methods

2.2.1. Preparation of Solid dispersions

5
Solid dispersions of IBU with HPMCAS and HPMCP-HP55 as the polymeric carriers were
prepared via spray drying (SD), electrospinning (ES) and rotary evaporation (RE) at differing
compositions as outlined in Table 1. DCM:MeOH at a ratio of 3:1 was used as the solvent for
all formulations. Previous work has demonstrated the suitability of this solvent ratio for both
IBU and the aforementioned excipients (Ziaee et al., 2017b).

Table 1; Composition of the samples prepared via spray drying, electrospinning and rotary evaporation techniques.

Sample composition IBU : HPMCAS or HPMCP-HP 55

1 1:9
2 3:7
3 5:5
4 7:3
5 9:1

Spray drying (SD): All spray drying experiments were performed on a Büchi B-290 mini
spray dryer in inert loop mode in conjunction with a condenser at −20 °C to facilitate the use
of organic solvents. A high efficiency cyclone was used to trap the spray dried particles once
formed. The 2-fluid nozzle utilised in this study had a 0.7 mm cap and an atomization gas
flow rate of ~357 NL/h (P = 1013.25 mbar and T = 273.15 K). An inlet temperature of 55 °C
and feed rate of 4.5 ml.min-1 was used for all samples. For spray drying, the process
parameters were selected based on the work done by Ziaee et al. and our observations during
spray drying process (Ziaee et al., 2017b). However, applying the inlet temperatures as high
as 70 °C for samples with over 20 wt.% ibuprofen led to high levels of stickiness. Therefore,
a lower temperature of 55 °C was selected as inlet temperature with lowest stickiness and
highest achievable yield for all samples. Due to the volatile nature of organic solvents,
nitrogen was selected as the atomizing gas. The aspirator was set to 100% (35 m3·h−1) for
circulating nitrogen as the drying gas. Dried powders were transferred to a desiccator
immediately after production and stored until further analyses.

Electrospinning (ES): Electrospinning was carried out under ambient conditions (24 ± 1°C
and relative humidity of 36.5 ± 3%). Samples were electrospun based on the optimized
parameters studied by L. Padrela et al.(Padrela et al., 2019). The solutions were sprayed
using a custom-built electrospinning device containing a plastic syringe with a metallic

6
needle. The needle was connected to a high voltage supply (Bertan, Series 230). Samples
were collected on grounded aluminium foils positioned 14 cm from the needle. The solution
was pumped at a flow rate of 15 ml.hr-1 at voltage of 15-20 kV. Deposited samples were
removed from the foil and stored in a desiccator until further analyses.

Rotary evaporation (RE): A Buchi R-100 rotary evaporator with a water bath temperature of
60 °C (based on the combined evaporation temperature of DCM and MeOH) was used for all
evaporation experiments. Samples were placed in a round bottomed flask and lowered into
the water bath with a rotational speed of 75 rpm. For all RE experiments the vacuum pump
was set to 722 mbar. After the majority of the solvent had been removed as indicated by the
lack of formation of droplets on the condenser rings, the vacuum was decreased to 500mbar,
followed by 250mbar, 50mbar and 5 mbar before the vacuum was released. Samples were
placed in a vacuum oven at 40 °C for 24 hours to remove any residual solvents. Samples were
milled and sieved by a 100 µm sieve and stored in a desiccator until further analyses.

2.2.2. Powder X-Ray diffraction (PXRD)

Sample were analysed using an X’pert PRO X-ray diffractometer (PANalytical, Almelo, the
Netherlands) with monochromatized Cu Kα radiation (λ=0.15405 nm) attached to a computer
running High Score Plus. The employed X-ray generator was set to 40 kV and 40 mA. Data
were collected over the 2θ range of 5–50°, with a step size of 0.02 °·step-1 and a step time of
40 s·step-1.

2.2.3. Thermal analysis

The residual solvent of all samples was analysed using a TGA-4000 Thermogravimetric
Analyser (Perkin-Elmer Instruments, Beaconsfield, Bucks, UK) at a heating rate of 10
°C·min−1 and a nitrogen purge gas flow rate of 30 mL.min-1.

A PerkinElmer Pyris I Differential Scanning Calorimeter (DSC) equipped with a refrigerated

cooling accessory (PerkinElmer, Workingham) using nitrogen as the purge gas (30
mL·min−1) was employed to evaluate the thermal transitions of the samples. Samples (∼5.0
mg) were weighed and placed in crimped DSC pans, then ramped from 20 to 200 °C at a
heating rate of 10 °C·min−1. Percentage crystallinity was calculated using the ratio of the area
under the endothermic melting peak in all processed samples and the area under the melting
peak of pristine IBU. Analysis was carried out using PE Pyris Thermal Analysis software,
version 10.1.

7
In order to investigate the amorphous and crystalline content of IBU in samples, the area
under the melting peak of IBU was calculated and used to quantify the amount of crystalline
IBU.

2.2.4. Scanning electron microscopy (SEM)

The morphology of all samples was investigated by high resolution field emission electron
microscopy (SEM, Hitachi SU-70) operating at 5 kV with 15 mm working distance. Samples
were coated with gold-palladium for 1 min with 20 mA current to avoid over-charging.

2.2.5. Spectroscopic analysis

Fourier transform infrared spectroscopy (FTIR): FTIR spectra were recorded at ambient
temperatures using a Perkin-Elmer Spectrum 100 FTIR spectrometer at wavelengths of
4000–650 cm−1 using an attenuated total reflection (ATR) accessory with a ZnSe crystal.
Samples were placed on the crystal with a pushing arm and 128 scans were collected at a
resolution of 4.00 cm−1.

Confocal Raman spectroscopy: Raman spectroscopy was carried out using a LabRAM HR
Evolution (HORIBA UK Ltd., Stanmore, UK) in a backscatter configuration with 785 nm
excitation, laser power 499 mW and exposure time of 10 s for 2 accumulations. Spectra were
collected using a 100x objective at a 4 cm−1 resolution from 717 to 1418 cm−1 using a grating
of 600 gr.mm−1. Spectral range was selected at the region which exhibited the greatest
variation for IBU-HPMCAS solid dispersions.

Hot stage Confocal Raman spectroscopy: Amorphous IBU was created in-situ on a
THMS600 microscope hot stage (Linkam Scientific, UK) by heating Form I crystalline IBU
at 10 °C.min-1 up to 80 °C and allowing cooling under ambient conditions.

Raman Mapping: Three dispersions of IBU-HPMCAS, prepared by ES, SD and RE were

analysed by Raman mapping on two separate days. For each map 160 spectra were collected
in a 8 by 20 rectangular arrangement with a spacing of 1 µm between points in both the x and
y axis. The Raman spectrometer included a 100x objective resulting in a laser spot size of
approximately 1µm.

Raman Spectral analysis: The full set of spectral data was analysed using R: A Language and
Environment for Statistical Computing (Team, 2013). Spectra were imported using a
customised import routine for the HyperSpec package followed by pre-processing including

8
transformation by Extended Multiplicative Signal Correction. Spectral variation was
illustrated using principal component analysis with consideration for the first five
components.

2.2.6. Density measurements

True density of all samples was measured at ambient temperature using the Accupyc II gas
displacement pycnometry system (Micromeritics®, Nocross, GA, USA) based on USP 699
standard procedure. Helium was purged into the sample chamber to determine its volume.
True density is the mass of a substance divided by its volume, excluding open and closed (or
blind) pores.

2.2.7. In vitro drug release studies

The dissolution studies were performed in sink condition following USP29 procedure for
IBU solubility studies in order to keep the results comparable and relevant to other work in
literature. USP II apparatus was employed with a paddle rotation speed of 50 rpm for 60 min.
Equivalent of 50 mg of IBU was added to each dissolution flask. Dissolution rates were
recorded in 900 mL of 0.1 M phosphate buffer with pH 7.2 (simulated gastrointestinal fluid)
which was equilibrated to 37 ± 0.5 °C. 5 mL samples were collected from the media and
filtered using Nylon 0.45 μm filters at specified intervals of 5, 10, 15, 20, 30, 45 and 60 min.

Preparation of standards and calibration curve

Stock solution of ibuprophen (1 mg/mL) was prepared in 1:1 (v/v) acetonitrile:0.1% (v/v)
orthophosphoric acid. Calibration curves (0.122 µg/mL – 250 µg/mL) were prepared by
subsequent dilution in the mobile phase.

Sample preparation

An aliquot of 500 μL of mobile phase was added to the same volume of each collected
dissolution sample. Diluted samples were then vortexed, filtered through 0.25µm syringe
filters and transferred to glass vials for analysis by HPLC.

HPLC analysis and quantification

HPLC was performed with an Agilent 1260 Infinity Series system (Agilent Technologies,
Waldbronn, Germany) equipped with a temperature-controlled column compartment and
DAD VL detector. The mobile phase consisted of 1:1 (v/v) acetonitrile and 0.1% (v/v)
orthophosphoric acid. Separations were performed on a Kromasil C18 5 μm, 4.6 d 250 mm

9
column (MZ-Analysentechnik GmbH, Mainz-Germany) at a flow rate of 1.0 mL/min. An
isocratic mobile phase (total run time 15 min) was used for the separation of IBU with an
injection volume of 10 μL. IBU was detected at a retention time equivalent to 7.805 min at a
wavelength of 195 nm with a limit of quantification (LOQ) of 0.122 µg/mL. Chromatography
data was collected and analysed by Agilent OpenLAB 2.2 chromatography data systems
(CDS) software.

2.2.8. N2 Adsorption

Nitrogen adsorption/desorption isotherms were measured at -196 °C using an Autosorb-1C

gas adsorption unit (Quantachrome Instruments, Boynton Beach, FL). Each sample was
degassed at 100 °C for 16 h under vacuum before starting the analysis. The linear part of
Brumauer-Emmett-Teller (BET) plots were used for determining the specific surface area of
samples. The adsorption of N2 adsorption/desorption isotherms was used for calculating the
pore size distribution using the conventional Barrett-Joyner-Halenda (BJH) method (Barrett
et al., 1951).

3. Results and discussion

3.1. Analysis of crystallinity

Figure 2 shows the PXRD patterns of all IBU-HPMCAS and IBU-HPMCP-HP55 samples
produced. Regardless of the processing techniques and type of excipient used, samples with
IBU:excipient ratios of 1:9 were all PXRD-amorphous, as no crystalline IBU peaks were
present. Alternatively, samples with excipient content <90 wt.% (3:7, 5:5, 7:3 and 9:1
IBU:excipient ratio) were partially crystalline. This was further investigated by DSC to
determine the percentage crystallinity of IBU in samples with different IBU:excipient ratios.
The stability of the spray dried samples was tested by PXRD analysis after 9 months of
storage in closed vials at room temperature (Figures S1 and S2). The results showed that all
ASDs were stable at the storage conditions.

10
Figure 2. Powder X-ray diffraction (PXRD) patterns of samples prepared by Electrospinning (ES), Rotary Evaporation (RS)
and Spray Drying (SD).

Pristine IBU has a single endothermic peak (melting point) at 75.45 °C as shown in Figure 3
(a) and (b). (Friesen et al., 2008; Ghosh et al., 2011). No melting peak was observed in RE,
SD and ES samples with 10 wt.% IBU, further highlighting the absence of any crystalline
IBU in these samples. Glass transition temperatures of HPMCAS and HPMCP-HP55 have
been reported at 120 °C and 138 °C, respectively The Tg of the amorphous IBU-HPMCAS-1-
9 was between 71-79 °C regardless of the processing technique used (Figure S3 and S4). In
amorphous samples of IBU-HPMCP-HP55-1-9 the detected Tg was observed between 62-64
°C. The large deviation in Tg between samples with differing excipients can be attributed to

11
the increased branching of HPMCAS in comparison with HPMCP-HP55. The crystalline
samples displayed melting points with onset temperatures from approximately 51 °C to 72 °C
(increasing with the percentage of IBU present in the samples). The presence of both
hydrogen bonding donor and acceptor groups in IBU molecule improves its hydrogen
bonding propensity with both polymers. However, a larger melting point depression in
samples prepared with HPMCAS highlighted the superior miscibility of IBU with HPMCAS
relative to HPMCP-HP55 (Donnelly et al., 2015). Based on research by Taylor and co-
workers on the evaluation of hydrogen bonding strengths in polymers, HPMCAS has very
strong hydrogen bonding donor strength, while HPMCP-HP55 has only strong hydrogen
bonding donor strengths (Van Eerdenbrugh and Taylor, 2011; Wegiel et al., 2013). The larger
melting point depression in samples containing HPMCAS could thus be correlated to the
presence of more and stronger hydrogen bonding donor groups compared with HPMCP-
HP55.

Figure 3; DSC thermograms of samples (a) electrospun IBU-HPMCAS samples and (b) electrospun IBU-HPMCP-HP55
samples (c) percentage of crystallinity of IBU present in formulations prepared via electrospinning, (d) percentage of
crystallinity of IBU present in formulations prepared via spray drying, (e) percentage of crystallinity of IBU present in
formulations prepared via rotary evaporation.

12
Figure 3 (c, d and e) shows the percentage of crystallinity for all samples and each processing
technique. The increase in the percentage of crystalline IBU at higher IBU contents was
observed in all samples. The solid dispersions which contained HPMCAS as the excipient
presented a lower crystalline content of IBU compared with the samples prepared by
HPMCP-HP55 as the excipient. This effect was only significant in samples with 5:5 and 7:3
IBU:excipient ratio. This is in accordance with the larger melting point depression observed
in these samples due to the more efficient and homogeneous distribution of IBU in the
presence of HPMCAS excipient. At low excipient contents i.e. 10 wt.% there was no
significant difference between excipients as the properties were mostly influenced by the
percentage of IBU present. Similarly, with 90 wt.% of excipient, no difference between the
amorphization strength of excipients was observed as the properties of samples were mainly
influenced by excipient concentration. Moreover, the lower Tg of HPMCAS compared with
HPMCP-HP55 and the presence of multiple hydroxyl and carboxyl functional groups as
hydrogen bond donor and acceptors led to a more homogeneous mixing with IBU during
processing.

Figure 4 shows the FTIR spectra of all samples and highlights the intermolecular interactions
between IBU and the respective excipients whereby the presence of specific interactions is
often used to infer miscibility and potential ASD formation (Marsac et al., 2006). Shifting of
FTIR vibrational peaks in ASD formulation spectra relative to pristine API and excipient, is
typically associated with intermolecular interactions due to hydrogen bonding.

The intense peak at 2955 cm-1 in the spectra of IBU is attributed to CH3 asymmetric
stretching. O-H and C=O of carboxylic acid and C-C stretching were assigned to the peaks at
2971 cm-1, 1721 cm-1 and 1231 cm-1, respectively. Moreover, the strong bond at 779 cm-1
corresponded to the rocking vibration of CH2. (Matkovic et al., 2005; Ramukutty and
Ramachandran, 2012; Ray et al., 2010). The sample with an IBU:excipient ratio of 1:9
presented the broadest peaks due to the presence of amorphous IBU irrespective of
processing technique. The narrow peaks at 1231 cm-1 and 1721 cm-1 in the samples
containing 3:7, 5:5, 7:3 and 9:1 IBU:excipient ratios, corresponds to the presence of
crystalline IBU. Moreover, the shifting in the position of the carboxyl peak at 1721 cm-1 to
higher wavenumbers by decreasing the IBU:excipient ratio, indicated the presence of
hydrogen bonding between the carboxylic acid group of IBU and the hydroxyl groups of
HPMCAS and HPMCP-HP55. Figures S11 and S12 show the FTIR spectra of rotary
evaporated and spray dried samples.

13
 Figure 4; FTIR spectra of samples produced via electrospinning (ES) using HPMCAS (a) and HPMCP-HP55 (b) as
excipient.

3.2. Morphology

Figure 5 shows the morphology of samples with 1:9 API to excipient ratio prepared via ES,
SD and RE. For each of the electrospun samples, fibres with diameters in the range of 1-3.5
µm were observed regardless of the type of excipient used (Figure 5 (a) and (b)). However,
samples produced with HPMCP-HP55 displayed increased beading relative to those produced
with HPMCP-HP55. This can be attributed to the differences in viscosity and surface tension
of the respective processing solutions. The fibrous morphology was gradually shifted to a
more crystalline appearance as the IBU content increased from 10 wt.% to 90 wt.% (see
Figures S7 and S8). Samples prepared via RE showed irregularly shaped particles for all
compositions (Figure 5 (c) and (d)) with IBU crystals clearly visible at higher IBU
concentrations (Figures S9 and S10). Dimpled and corrugated spherical particles were
observed in spray dried samples with up to 30 wt.% IBU (Figure 5 (e) and (f)). Needle-
shaped crystals were present in samples with more than 50 wt.% IBU (Figures S11 and S12).
These observations suggest the effect of polymeric excipient on formation of spherical
particles. Moreover, the low Tg, (i.e. low viscosity) of IBU at high temperatures during spray
drying led to formation of large agglomerates in samples with >70 wt.% IBU, with particle
sizes ranging from 5-15 µm. Particle morphology is a key consideration in optimizing the
downstream processing of ASDs specifically as solid oral dosage forms such as tablets.

14
 Figure 5; SEM images of samples with 1:9 API to excipient ratio: (a) ES-IBU-HPMCP-HP55, (b) ES-IBU-HPMCAS, (c)
RE-IBU-HPMCP-HP55, (d) RE-IBU-HPMCAS, (e) SD-IBU-HPMCP-HP55, (f) SD-IBU-HPMCAS.

3.3. In vitro dissolution

Figure 6(a) shows the dissolution rate profile of the samples with the same composition (10
wt.% IBU) in a simulated gastrointestinal fluid (phosphate buffer, pH~7.2). Results show that
the dissolution rate of IBU in all samples was increased regardless of the preparation
technique used when compared with pristine IBU. The fastest release profile was observed
for each of the electrospun samples. Over 65% of the drug was released from electrospun
samples in the first 5 minutes while only 50 % and 40 % was released from spray dried and
rotary evaporated samples, respectively. In order to check the statistical significance of the
difference between the dissolution rate of samples after 5 minutes, a t-Test was performed. A
P-value of 0.047 (P-value<0.05) revealed the meaningful difference of the dissolution rate
values. Despite the slow initial release in SD and RE samples, all samples released over 65 %
of the API after 50 minutes. The enhanced dissolution properties of samples prepared by ES
has previously been observed and can be attributed to the presence of micro and nano-scale
fibres (Nagy et al., 2015a). To further investigate the enhanced dissolution profile of the
electrospun samples the specific surface area of each sample was determined.

15
 Figure 6. (a) Dissolution rate profile of ES/RE/SD-IBU-HPMCCP-HP55 and ES/RE/SD-IBU-HPMCAS samples (API-
excipient 1:9 ratio), (b) Adsorption/desorption isotherms of ES/RE/SD-IBU-HPMCP-HP55-1:9 samples.

Figure 6(b) shows the N2 adsorption/desorption isotherms of three samples of ES/RE/SD-

IBU-HPMCP-HP55 with an IBU:excipient ratio of 1:9. The calculated specific surface area
of each sample is reported in Table 2. The specific surface area of ES sample was 2 and 15-
fold larger than the SD and RE samples respectively, which subsequently led to its relatively
faster dissolution rate. The direct correlation of dissolution rate and surface area of solute was
previously explained by well-known Noyes-Whitney equation (Noyes and Whitney, 1897).

Table 2; Specific surface area of samples prepared via ES, SD, and RE containing 10 wt.% IBU.

Sample Specific Surface Area (m2/g)

ES-IBU-HPMCP-HP55-1-9 31.47
SD-IBU-HPMCP-HP55-1-9 13.05
RE-IBU-HPMCP-HP55-1-9 1.97

3.4. Intermolecular Interactions

3.4.1. Raman spectroscopy

To investigate the effect of processing techniques on the solid state form of IBU, hot stage
Raman was used to prepare samples of amorphous IBU in situ (Rehder et al., 2013). Form I
crystalline IBU melted in line with the reported melting point of IBU of 79 °C (Figure 7 (a)).
When the liquid form was allowed to cool under ambient conditions, the collected spectrum
matched that of amorphous IBU which was previously reported by Rehder et al. and Hédoux
et al. (Hédoux et al., 2011; Rehder et al., 2013). The glassy form of IBU was extremely

16
unstable at room temperature and started to re-crystallise in less than an hour thereby further
highlighting the challenges of preparing stable ASDs of IBU.

The Raman spectrum of amorphous IBU was used for tracking its dispersion in each of the
different samples. The spectra collected from each ASD of IBU-HPMCAS with a 1:9 ratio
were averaged point by point to provide a representative spectrum of the whole dispersion
and are shown in Figure 7(b) along with the spectra of pure crystalline and amorphous IBU
and HPMCAS. The spectrum of the dispersion is mostly similar to that of HPMCAS apart
from two regions marked in grey (Figure 7(b)) between 775-875 cm-1 and 1160-1235 cm-1,
respectively. Specifically, the peak at 1187 cm-1 confirms that the IBU is present in the
amorphous form in all samples.

(a) (b)

Figure 7; (a) Raman spectra of (i) Form I IBU at 30 °C, (ii) Form I IBU at 70 °C, (iii) Melted IBU at 80 °C, (iv)
supercooled glassy IBU at 50 °C, (v) Form I IBU which recrystallized from the glass in under one hour at room
temperature, (b) Raman spectra of form I IBU, amorphous IBU, HPMCAS and the spray dried, electrospun and rotary
evaporated samples.

3.4.2. Influence of processing technique on homogeneity of solid dispersions

The differentiation of ASDs with similar overall amorphous content, but different
stability/dissolution qualities has previously been investigated by Benes et al. (Beneš et al.,
2017). Analysis techniques such as PXRD and DSC are well established for the measurement
of bulk ASD properties (Nollenberger et al., 2009). However, the determination of
homogeneity on a localised scale is required for a comprehensive understanding of the
influence of processing technique on the stability of ASDs over long-term storage (Lauer et
al., 2013). Confocal Raman Spectroscopy was employed to determine the homogeneity of

17
samples that contained the same formulation (API:excipient ratio 1:9) but had been prepared
by different processing techniques.

Figure 8. Plot of the spread of Raman spectra collected from three similarly composed but differently prepared solid
dispersion.

Principle component analysis (PCA) was performed on the spectral window between 775-875
cm-1 and 1160-1235 cm-1 where the spectra are different than that of HPMCAS. The K-mean
clustering analysis was employed to group the spectra according to their similarity, forming
clusters with each cluster representing identical molecular properties. Thus, a wider spread of
the clusters is a clear sign of sample heterogeneity. PC2 represents 4.8 % of the variance
whereas PC3 represents 1.7% of the variations thereby permitting easier sample
differentiation on the PC2 scale. Figure 8 shows the spread of Raman spectra collected from
three similarly composed but differently prepared ASDs. 95% confidence ellipses are added
to aid visualisation based on the scaled and mean centred scores of the second and third
principal components. This plot shows that the greatest variation is in the spectra collected
from the electrospun samples, followed by the spray dried dispersions, with the least variable
dispersion produced by rotary evaporation. Although the electrospun samples had

18
substantially higher dissolution rate due to their larger specific surface area, low
compositional homogeneity could significantly affect their stability during long term storage.

4. Conclusions

Three different solvent-based ASD processing techniques, spray drying, electrospinning and
rotary evaporation were evaluated for the preparation of ASDs of IBU with polymers of
HPMCAS and HPMCP-HP55. Results show that the complete transformation of crystalline
to amorphous IBU is exclusively composition dependent regardless of the processing
technique used. Electrospun ASD samples displayed higher dissolution rates compared with
samples produced via RE and SD. Morphological analysis revealed the significant effect of
specific surface area on dissolution rate. Moreover, HPMCAS was defined as a relatively
stronger ASD former compared with HPMCP-HP55 due to its higher Tg, higher melting point
depression and increased abundance of appropriate functional groups suitable for hydrogen
bonding. Confocal Raman spectroscopy was employed to assess the homogeneity of ASDs as
a critical factor for their stability. The highest levels of inhomogeneity were observed in
samples produced by ES followed by SD and RE, which should be considered for assessing
the long-term stability of ASDs. This study shows the significance of preparation technique
in altering the critical properties of ASDs such as dissolution rate, specific surface area and
homogeneity. Enhancing these physicochemical properties could lead to more robust and
improved downstream processing strategies.

Notes

The authors declare no competing financial interests.

Acknowledgements

This work was funded under Science Foundation Ireland grant “Modelling of Multiphase
Transport Automation in Manufacturing, (MOMEnTUM)” - (14/SP/2750)

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