Preparation and Characterization of Solid Dispersion Using a Novel Am-
phiphilic Copolymer to Enhance Dissolution and Oral Bioavailability of
Sorafenib

Duy Hieu Truong, Tuan Hiep Tran, Thiruganesh Ramasamy, Ju Yeon

Choi, Han-Gon Choi, Chul Soon Yong, Jong Oh. Kim

PII: S0032-5910(15)00329-0
DOI: doi: 10.1016/j.powtec.2015.04.044
Reference: PTEC 10954

To appear in: Powder Technology

Received date: 29 December 2014

Revised date: 12 February 2015
Accepted date: 20 April 2015

Please cite this article as: Duy Hieu Truong, Tuan Hiep Tran, Thiruganesh Ramasamy,
Ju Yeon Choi, Han-Gon Choi, Chul Soon Yong, Jong Oh. Kim, Preparation and
Characterization of Solid Dispersion Using a Novel Amphiphilic Copolymer to En-
hance Dissolution and Oral Bioavailability of Sorafenib, Powder Technology (2015), doi:
10.1016/j.powtec.2015.04.044

This is a PDF file of an unedited manuscript that has been accepted for publication.
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 ACCEPTED MANUSCRIPT

Preparation and Characterization of Solid Dispersion Using a Novel Amphiphilic

Copolymer to Enhance Dissolution and Oral Bioavailability of Sorafenib

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Duy Hieu Truonga, Tuan Hiep Trana, Thiruganesh Ramasamya, Ju Yeon Choia,

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Han-Gon Choib, Chul Soon Yonga,**, Jong Oh Kima,*

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a
College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyeongsan 712-749,

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South Korea.
b
College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang
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University, 55, Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, South Korea.
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*
Corresponding author: Prof. Jong Oh Kim, Ph.D.,

Tel: +82-53-810-2813, Fax: +82-53-810-4654

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E-mail:jongohkim@yu.ac.kr

**
Co-corresponding author: Prof. Chul Soon Yong, Ph.D.

Tel: +82-53-810-2812, Fax: +82-53-810-4654

E-mail:csyong@ynu.ac.kr

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Abstract

The objective of the current study was to enhance dissolution and oral bioavailability of

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the poorly water-soluble drug, sorafenib (SFN), by solid dispersion (SD) technique using a

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novel amphiphilic copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol

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graft copolymer (Soluplus®). The SD formulations were prepared by the spray drying

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method with SFN, Soluplus, and sodium lauryl sulfate (SLS) at various weight ratios in

water. The optimized SD formulation, which showed the highest dissolution rate in

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distilled water, was further characterized for surface morphology, crystallinity, dissolution

in pH 1.2, pH 4.0, pH 6.8, and pharmacokinetics in rats. Powder X-ray diffraction and
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differential scanning calorimetry revealed the amorphous form of SFN in the formulation.

In addition, at the oral dosage of 20 mg/kg SFN, the SD formulation showed increased
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Cmax and AUC0–48h by 1.5- and 1.8-fold, compared to those of SFN powder, respectively
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(p<0.05). These findings suggest that the preparation of SFN-loaded SD using Soluplus

could be a promising strategy for improvement of oral bioavailability of SFN.

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Keywords: sorafenib, soluplus, solid dispersion, dissolution, solubilization.

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1. Introduction

Sorafenib (SFN), a novel bi-aryl urea derivative, strongly inhibits Raf-1, a member

of the RAF/MEK/ERK signaling pathway. SFN targets several serine/threonine kinases

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and receptor tyrosine kinases, including vascular endothelial growth factor receptor

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(VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-β, Flt-3, and c-

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KIT, which are related to tumor cell proliferation and angiogenesis [1, 2]. It has been

approved by the U.S. Food and Drug Administration (US-FDA) for treatment of patients

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with advanced renal cell carcinoma, unresectable hepatocellular carcinoma, and

differentiated thyroid carcinoma [3, 4]. According to the Biopharmaceutical classification

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system (BCS), SFN belongs to BCS class II, which is characterized by low solubility and

high permeability. SFN has very poor solubility in aqueous media at various pH values
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from pH 1.2 to pH 7.4 [5-8]. This leads to slow dissolution rate in the gastrointestinal tract,

which is supposed to be the rate-limiting step for absorption and together with the first-
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pass metabolism results in low bioavailability and large inter-subject variability [9, 10].
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Therefore, some formulation strategies have been developed to enhance the

physiochemical properties and improve the bioavailability of the drug [7, 8].
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Solid dispersion (SD) is a simple and well-studied approach to increase the

dissolution rate and bioavailability of poorly water-soluble drugs [11-21]. By definition, a

pharmaceutical SD is a product prepared by transforming a drug-carrier combination into

the solid state from the original fluid state [22]. Hydrophilic polymers are the most

frequently used carriers for fabrication of SDs [23]. Selection of the right carrier(s) for

formulation of the SD is very important. Recently, interest in use of Soluplus® as the

matrix carrier in the SD system has increased [24, 25]. Soluplus is a novel graft copolymer

initially designed for solid solutions by hot-melt extrusion [26]. Due to its amphiphilic

chemical structure, it has bifunctional properties as a matrix polymer for solid solutions
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and an active solubilizer with the ability to enhance solubility of poorly water-soluble

drugs.

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In this study, SFN-loaded SDs were prepared with Soluplus and sodium lauryl

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sulfate by the spray-drying method. Scanning electron microscopy (SEM), differential

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scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were then applied in

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order to characterize the physicochemical properties of the optimal solid dispersion

formulation. In addition, a pharmacokinetic study was conducted in order to compare the

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effect of the solid dispersion on the bioavailability of the drug with the pure SFN powder.
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2. Materials and Methods

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2.1 Materials
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Sorafenib tosylate was purchased from Green Stone Swiss Co., Ltd (China).
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Hydroxypropylmethyl cellulose (HPMC 2910), Polyvinylpyrrolidone (PVP K30),

Polyoxyl 40 hydrogenated castor oil (Cremophor® RH40), Polyoxypropylene –

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polyoxyethylene block copolymer (Poloxamer 407, Poloxamer 188) and polyvinyl

caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) were

purchased from BASF (Ludwigshafen, Germany). Polysorbate 20 (Tween 20), polysorbate

80 (Tween 80), and sodium lauryl sulfate (SLS) were purchased from Duksan Chemical

Co., Ltd. (Ansan, Korea). Polyoxyethylene 10 stearyl ether (Brij 76) and polyoxyethylene

20 cetyl ether (Brij 58) were purchased from Sigma-Aldrich, Korea. All other chemicals

and reagents were of analytical grade and used without further purification.

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2.2. Solubility study

The solubility study of SFN was performed according to the following procedure.

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Excessive amounts of SFN were added to 1 mL of aqueous solutions containing 1% carrier

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(w/v) in 2 mL capped tubes. These tubes were vortexed for 30 seconds and shaken at 37 ±

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0.5°C for 72 hours in a thermostatically controlled water bath, then centrifuged at 10000 x

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g for 10 minutes (5415C, Eppendorf, USA). The supernatant layers were filtered through a

0.45-μm membrane filter (Whatman, UK), and the SFN concentrations were analyzed by

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HPLC with prior suitable dilution.
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2.3. Preparation of SFN-loaded SD

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SD formulations of SFN were prepared using a Büchi 190 nozzle-type mini spray
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dryer (Flawil, Switzerland). Various amounts of Soluplus and SLS were dissolved in

distilled water. Then, SFN was dispersed into these solutions and the resulting dispersions
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were spray dried under the following conditions: inlet temperature, 130 °C; resulting outlet
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temperature, 70-75°C; feeding rate, 3 mL/min, which delivered the dispersions to a

pneumatic nozzle (diameter of 0.7 mm) via a peristaltic pump; aspiration, 80%; spray

pressure, 4 kg/cm2; drying air flow, 600 L/h. The direction of air flow was the same as that

of sprayed products [11, 27-29]. The suspensions were stirred continuously by magnetic

stirrers during the spray drying process. The physical mixture was prepared by mixing the

same weight ratio of the SD formulation using a mortar and a pestle.

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2.4. Dissolution study

In vitro dissolution study of SFN powder and SFN-loaded SD formulations was

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carried out using USP dissolution apparatus 2 (Universal Scientific Co., Ltd, Seoul, Korea)

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in four media of 900 mL containing 0.1% Tween 80: distilled water, hydrochloric acid

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solution (pH 1.2), acetate buffer solution (pH 4.0), and phosphate buffer solution (PBS, pH

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6.8). Capsules (size 0) were filled with the drug powder and drug-loaded SDs (equivalent

to 10 mg SFN powder) and placed in sinkers before dropping into the dissolution media.

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The dissolution media were maintained at 37 ± 0.5°C and stirred at the paddle speed of 50

rpm. At the predefined time points, 3 mL of the dissolution media was withdrawn, filtered
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through a 0.45-μm membrane filter and immediately replaced by the same volume of fresh

dissolution media. The concentrations of dissolved SFN were analyzed using the HPLC
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method as described below. All measurements were performed in triplicate.

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2.5. Drug analysis

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The drug concentrations were analyzed using a Hitachi HPLC system that

comprised of a pump (Model L-2130), and an ultraviolet detector (Model L-2400).

Measurement was performed on a Cosmosil® C18-AR-II column: 5 μm, 4.6 x 150 mm

(Nacalai Inc., USA). The mobile phase, consisting of methanol, acetonitrile, and 1% acetic

acid solution (40:35:25, v/v) was eluted at the flow rate of 1.0 mL/min. The effluent was

detected at the wavelength of 265 nm.

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2.6. Characterization of solid dispersion

2.6.1. Shape and surface morphology

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Scanning electron microscopy (SEM) was used to examine the surface morphology

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of SFN, and the SD formulation (F5) with a scanning electron microscope (S-4100,

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Hitachi, Japan). The samples were attached to a metal sample holder using double-sided

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adhesive tape and then made electrically conductive by coating with platinum (6 nm/min)

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in a vacuum (6 Pa) using Hitachi Ion Sputter (E-1030) for 120 s at 15 mA prior to

observation.
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2.6.2. Powder X-ray diffraction (PXRD)

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The PXRD patterns of SFN powder, Soluplus, SLS, the physical mixture, and the
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SD formulation (F5) were recorded using an X’Pert PRO MPD diffractometer

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(PANalytical, Almelo, the Netherlands) with CuKα radiation (λ = 1.54 Å). The operating

voltage and current were 40 kV and 30 mA, respectively. Diffractograms were obtained in
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the angular range 2θ (diffraction angle) from 10° to 60° with a step size of 0.02626°.

2.6.3. Differential scanning calorimetry (DSC)

Thermal analysis of the drug powder, SLS, Soluplus, the physical mixture, and the

SD formulation was performed using a differential scanning calorimeter (DSC-Q200, TA

Instruments, USA). Accurately weighed samples (approximately 2-3 mg) were sealed in an

aluminium pan. The scans were performed over the temperature range of 40–250°C at a

heating rate of 10 °C/min, under a nitrogen purge at a flow rate of 50 mL/min. The

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temperature and enthalpy of the DSC system were calibrated using a standard aluminum

pan.

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2.7. Pharmacokinetics

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All animal care procedures were performed according to the Guiding Principles in

the Use of Animals in Toxicology as amended in 2008 by the Society of Toxicology [30].

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The study protocols were approved by the Institute of Laboratory Animal Resources of

Yeungnam University.
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Male Sprague-Dawley rats weighing 280 ± 20 g were fasted overnight prior to the

experiments with free access to water. Six rats were randomly divided into two groups
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(n=3). Each rat was anaesthetized by diethyl ether, and the right femoral artery was
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cannulated for insertion of a polyethylene tube. The drug powder and the SFN-loaded SD

formulation were dispersed into water, and administered orally to the rats in each group at
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the dosage of 20 mg/kg SFN [9, 31]. Then, approximately 0.3 mL of blood was collected
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from the cannulated artery at predefined time intervals into heparinzed tubes, and

centrifuged at 10,000 x g for 10 min (5415C, Eppendorf, USA). The supernatant layers

were collected and stored frozen at −20 °C until analysis.

The drug analysis was adapted from a previous method with a slight modification

[7]. Plasma (40 μL) and acetonitrile (260 μL) were mixed and vortexed. The mixtures were

then centrifuged at 10,000 × g for 10 min and the supernatant layers were collected. The

drug concentration in the supernatant layers was analyzed using the HPLC method as

described above. The standard calibration curve showed excellent linearity (r = 0.999) in

the concentration range of 0.1 - 20 µg/mL of SFN in plasma.

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Pharmacokinetic parameters, including the area under the plasma concentration

versus time curve from zero to 48h (AUC0→48h), the elimination rate (Kel) and half-life (t1/2)

were calculated by non-compartmental analysis using WinNonlin® software (version 2.1;

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Pharsight Co., Mountain View, CA, USA). The maximum plasma concentration (Cmax)

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and the time taken to reach Cmax (Tmax) were obtained directly from plasma data.

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2.8. Statistical analysis

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Statistical analysis of the samples was performed using a Student’s t-test. A p-value
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< 0.05 was considered to indicate statistical significance. All data were presented as the

mean ± standard deviation, unless otherwise stated.

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3. Results and discussion

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3.1 Solubility studies

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Excipient screening for the poorly water-soluble drug, SFN, can be considered as

the first step in development of SD formulation [32]. Thus, a solubility study of SFN in

various solutions of hydrophilic polymers and surfactants was performed for selection of

suitable carriers for the SFN-loaded SD (Table 1). Among the hydrophilic polymers tested,

Soluplus exhibited the highest solubility of the drug (0.701 ± 0.072 mg/mL). Among the

surfactants tested, SLS showed the highest solubility of the drug (1.838 ± 0.194 mg/mL).

Therefore, Soluplus and SLS were selected as the carriers in the SD formulations.

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3.2. Optimization of SFN-loaded SD

Various formulations of SFN-loaded SD were prepared using a spray drier with

water, a hydrophilic polymer (Soluplus®) and a surfactant (SLS). Briefly, solutions of

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Soluplus and SLS were prepared in distilled water and SFN was dispersed in these

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solutions. After stirring for about 1 h at 37°C, the homogenous suspensions were spray-

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dried. To measure the effect of drug/carrier ratio, different SD formulations with varying

drug/carrier ratios and fixed amount of SLS were prepared (Table 2).

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In order to understand the effect of drug/carrier ratio on SFN-loaded SD, the
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dissolution profiles of SFN from SD were investigated. As shown in Fig. 1, all of the

formulations showed significantly higher dissolution rate than the SFN powder (p < 0.05).
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However, at the drug/carrier ratio of 1/5, formulation F3 exhibited significantly higher

drug release after 120 min than formulations F1 and F2 with the drug/carrier ratio of 1/1
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and 1/3, respectively (p < 0.05). Therefore, the drug/carrier ratio of 1/5 was used to further
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evaluate the effect of Soluplus/SLS ratio on the dissolution rate. When the amount of SLS

was increased, the release was increased and reached approximately 100% at the
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drug/Soluplus/SLS ratio of 1/4.5/0.5 in formulation F5. Thus, formulation F5 was chosen

as the optimal formulation for further studies.

3.3. Characterization of the solid dispersion

The surface morphology of SFN powder and SFN-loaded SD was visualized by SEM (Fig.

2). As shown in Fig. 2A, the pure drug appeared as rectangular crystals ranging in size

from 10 to 100 μm, while the solid dispersion formulation contained relatively rough

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surfaced particles (Fig. 2B). These results suggested that the carriers might be attached to

the surfaces of the drug particles.

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The crystallinity of the SFN powder, Soluplus, SLS, the physical mixture, and the

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solid dispersion formulation were determined by PXPD analysis. Typical diffraction

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patterns of SFN, Soluplus, SLS, the physical mixture, and sorafenib-loaded solid

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dispersion are shown in Fig. 3. The diffraction pattern of pure SFN showed various

characteristic 2θ peaks at 13.2°, 17.8°, and 21.5°, revealing a highly crystalline structure.

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However, these distinctive peaks of SFN were absent in the pattern of the solid dispersion,

indicating that the drug may be in the amorphous form or molecularly dispersed in the
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carrier matrix.
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In addition, the thermal behaviors of SFN powder, Soluplus, SLS, the physical

mixture, and SFN-SD formulation were further characterized by DSC (Fig. 4). The DSC
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curve of SFN displayed one large, sharp endothermic peak at about 238 °C, which
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corresponds to the melting point of the tosylate salt form and one small endothermic peak

at about 200 °C which might be relevant to the melting point of the sorafenib base form.
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The same phenomenon was observed in another study [33]. However, these peaks

disappeared in the curve of the solid dispersion which confirms the molecular dispersion of

sorafenib in the carrier matrix.

The high melting point of the drug is one of the causes of poor aqueous solubility

[34]. Thus, any strategy that disrupts the crystalline nature and/or reduces the crystal lattice

energy such as solid-state dispersion of the drug into water-soluble carrier matrix would

result in a partial or total loss of crystallinity, thereby increasing the aqueous solubility of

the drug. For this approach, the water-soluble polymer Soluplus® has succeeded in

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inhibiting the crystallization of drugs, forming amorphous solid dispersions with enhanced

drug solubility and dissolution rate [24, 25].

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The dissolution profiles of the optimal SD formulation were compared with those

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of SFN powder in the three dissolution media (pH 1.2, pH 4.0, and pH 6.8) (Fig. 5). In all

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media tested, SFN had low dissolution rates because of its low aqueous solubility in these

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media and hydrophobic surface. At pH 1.2, the percentage of pure SFN dissolved in 120

min was significantly higher than those in distilled water and other pH conditions (p <

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0.05). This was because the aqueous solubility of SFN is pH-dependent with lower pH

resulting in higher solubility. On the contrary, the SD formulation exhibited significantly

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higher dissolution rates due to the enhanced solubility and increased wettability/surface

hydrophilization resulting from the attachment of hydrophilic carriers (p < 0.05) [23].
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3.4. Pharmacokinetic study

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The pharmacokinetic profile of the SFN-loaded SD formulation was compared

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with that of SFN powder in rats. The mean plasma concentration of SFN versus time

profiles after oral delivery of SFN powder and SFN-loaded SD formulation at the dose of

20 mg/kg of SFN are shown in Fig. 6, and the pharmacokinetic parameters (Cmax, Tmax,

AUC, Kel, t1/2) are summarized in Table 3. The SD formulation showed significantly

higher plasma concentration compared to the powder (p < 0.05). The Cmax (5.24 ± 0.40

µg/mL) and AUC (150.01 ± 33.96 h.µg/mL) values of the SD group were 1.5-fold and 1.8-

fold higher than those of the SFN powder group, respectively. The enhanced oral

bioavailability of SFN in the SD formulation might be due to the noticeable improvement

in the dissolution rate and subsequent absorption of the drug in rats.

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4. Conclusion

The SD formulations of SFN with the use of a novel amphiphilic copolymer,

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Soluplus®, were successfully prepared by the spray drying technique. The preparation

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process does not require use of organic solvents that are toxic and unsafe. The drug was

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changed from a crystalline form into an amorphous form in solid dispersion. The SFN-

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loaded SD formulations markedly increased the dissolution rate of the drug. In addition,

the pharmacokinetic study in rats showed significantly higher oral bioavailability of SFN

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in the SD formulation group, compared with the SFN powder group. Therefore, SFN-
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loaded SD using the amphiphilic polymer Soluplus® could be an effective approach to

delivery of SFN with enhanced bioavailability.

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Acknowledgements
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This research was supported by Yeungnam University research grants in 2014.

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Figure legends

Fig. 1. Dissolution profiles of sorafenib powder, F1, F2, F3, F4 and F5 in distilled water.

Fig. 2. SEM images of (A) sorafenib powder, and (B) SD formulation (F5).

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Fig. 3. X-ray powder diffraction of Sorafenib powder, Soluplus, sodium lauryl sulfate

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(SLS), the physical mixture, and SD formulation (F5).

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Fig. 4. Differential scanning calorimetric thermograms of sorafenib powder, Soluplus,

Sodium lauryl sulfate (SLS), the physical mixture and SD formulation (F5).

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Fig. 5. Dissolution profiles of the drug from capsules containing sorafenib powder or the

solid dispersion at (A) pH 1.2, (B) pH 4.0, and (C) pH 6.8 media. The SD formulation (F5)
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was composed of sorafenib/Soluplus/SLS at the weight ratio 1/4.5/0.5. Each value

represents the mean ± standard deviation (n=3).

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Fig. 6. Plasma concentration-time profiles of sorafenib in rats after oral administration of

sorafenib powder and sorafenib-loaded SD formulation (F5). Data are presented as the
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mean ± standard error (n = 3).

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Table 1. Aqueous solubility of sorafenib.

Carrier Aqueous solubility (mg/mL)

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Water N/A

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Hydrophilic polymers

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HPMC 2910 0.097 ± 0.001

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PVP K30 0.095 ± 0.001

Soluplus 0.701 ± 0.072

Surfactants
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Sodium lauryl sulfate 1.838 ± 0.194

Poloxamer 407 0.076 ± 0.013

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Poloxamer 188 0.097 ± 0.001

Brij 76 0.181 ± 0.004

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Brij 58 0.243 ± 0.023

Cremophor RH40 0.203 ± 0.004

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Tween 20 0.095 ± 0.009

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Tween 80 0.123 ± 0.014

Each value represents the mean ± standard deviation (n=3).

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Table 2. Compositions of sorafenib-loaded solid dispersion formulations.

Ingredients (g) F1 F2 F3 F4 F5

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Sorafenib 1 1 1 1 1

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Soluplus 0.9 2.9 4.9 4.75 4.5

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SLS 0.1 0.1 0.1 0.25 0.5

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Drug/carrier (w/w) 1/1 1/3 1/5 1/5 1/5

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Table 3. Pharmacokinetic parameters of sorafenib in rats after oral administration of

sorafenib powder or the SD formulation (F5).

Parameters Powder SD formulation (F5)

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Cmax (µg/mL) 3.38 ± 0.73 5.25 ± 0.40*

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Tmax (h) 4.00 ± 2.00 4.00 ± 0.00

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AUC (h.µg/mL) 82.01 ± 24.56 150.01 ± 33.96*

Kel (h-1) 0.036 ± 0.002 0.028 ± 0.004

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t1/2 (h) 19.37 ± 1.16 25.16 ± 3.26
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Each value represents the mean ± standard deviation (n=3).
* p < 0.05 compared with sorafenib powder.
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Figure 1

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Figure 2

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(A) (B)

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Figure 3

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Figure 4

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Figure 5

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Figure 6

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Graphical abstract
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Highlights

We prepared sorafenib (SFN) solid dispersion by spray drying technique.

Solid dispersion was prepared using the amphiphilic polymer Soluplus.

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The SFN-loaded solid dispersion markedly increased the dissolution rate of SFN.

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It could be an effective approach to delivery of SFN with enhanced bioavailability.

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