Drug Design, Development and Therapy

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Applying Different Techniques to Improve

the Bioavailability of Candesartan Cilexetil
Antihypertensive Drug

Usama Farghaly Aly, Hatem Abdel-monsef Sarhan, Taha F S Ali & Hosny Abd
El-Bakey Sharkawy

To cite this article: Usama Farghaly Aly, Hatem Abdel-monsef Sarhan, Taha F S Ali & Hosny
Abd El-Bakey Sharkawy (2020) Applying Different Techniques to Improve the Bioavailability
of Candesartan Cilexetil Antihypertensive Drug, Drug Design, Development and Therapy, ,
1851-1865, DOI: 10.2147/DDDT.S248511

To link to this article: https://doi.org/10.2147/DDDT.S248511

© 2020 Aly et al.

Published online: 14 May 2020.

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ORIGINAL RESEARCH

Applying Different Techniques to Improve the

Bioavailability of Candesartan Cilexetil
Antihypertensive Drug
This article was published in the following Dove Press journal:
Drug Design, Development and Therapy

Usama Farghaly Aly 1 Purpose: The objective of this study was to compare different techniques to enhance the
Hatem Abdel- solubility and dissolution rate, and hence the bioavailability of candesartan cilexetil.
monsef Sarhan 1 Methods: To achieve this target, various techniques were employed such as solid disper-
Taha FS Ali 2 sions, inclusion complexes, and preparation of candesartan nanoparticles. Following the
preparations, all samples were characterized for their physicochemical properties, and the
Hosny Abd El-
samples of the best results were subjected to further bioavailability studies.
Bakey Sharkawy 1
Results: Results of dissolution studies revealed an increase in the dissolution rate of all
1
Department of Pharmaceutics, Faculty of samples. The highest dissolution rate was achieved using solid dispersion of the drug with
Pharmacy, Minia University, Minia, Egypt;
2
Department of Medicinal Chemistry, PVP K-90 (1:4). Physicochemical investigations (XR, DSC, and FT-IR) suggested formation
Faculty of Pharmacy, Minia University, of hydrogen bonding and changing in the crystalline structure of the drug. Regarding the
Minia, Egypt inclusion complexes, more stable complex was formed between HP-β-CD and CC compared
to β-CD, as indicated by phase solubility diagrams. Antisolvent method resulted in the
preparation of stable nanoparticles, as indicated by ζ potential, with average particle size
of 238.9 ± 19.25 nm using PVP K-90 as a hydrophilic polymer. The best sample that gave
the highest dissolution rate (CC/PVP K-90 1:4) was allowed for further pharmacokinetic
studies using UPLC MS/MS assay of rabbit plasma. Results showed a significant increase in
the bioavailability of CC from ~15% to ~48%.
Conclusion: The bioavailability of CC was significantly improved from ~15% to ~48%
when formulated as SDs with PVP K-90 with 1:4 drug:polymer ratio.
Keywords: solid dispersion, inclusion complex, nanoparticles, pharmacokinetics, UPLC
MS/MS

Introduction
Hypertension is one of the most prevalent cardiovascular disorders that affect
millions of peoples around the world. Growing evidences indicated the strong
relationship between hypertension and increasing the risk of coronary heart diseases
and the incidence of stroke.1
Candesartan cilexetil (CC) is an angiotensin II receptor blocker and one of the
most prevalent antihypertensive drugs. It is also indicated in the management of
Correspondence: Usama Farghaly Aly
Department of Pharmaceutics, Faculty of other cardiovascular disorders as congestive heart failure.2–6 Chemically, it is
Pharmacy, Minia University, Assuit a tetrazole derivative which is clinically used in the form of an ester prodrug
Agriculture Road, P.O: 61519, Minia,
Egypt (Figure 1). During the absorption from GIT, CC is bioactivated by ester hydrolysis
Tel +20 100110868 and liberates the free drug.7 It is characterized by poor aqueous solubility and low
Fax +20 862369075
Email [email protected] dissolution rate which resulted in a very low bioavailability, only 15%.5,8,9

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inclusion complex. Among these parameters, stability con-

stant (Kc) is crucial for determining the degree of complex
stability. Contrary to what is believed, very stable complexes
represent great obstacle against the absorption of drugs from
GIT,21,22 while complexes with lower values of Kc are
unstable, and both of them have limited industrial
applications.
Recently, nanotechnology has been introduced to
Figure 1 Structure of candesartan.
improve the solubility and the dissolution velocity of
water-insoluble drugs. There are two main approaches
for the preparation of drug nanoparticles: the first is a top-
In order to improve the solubility of such drugs, many
down process which includes comminution of particles to
scientists employed different techniques; among them,
smaller size and the second is bottom-up processes that
solid dispersions, inclusion complexations, and recently
involve nucleation of particles from the molecular state.23
nanotechnology are efficient and most widely used. Solid
However, aggregation of particles is still the major disad-
dispersions are traditionally defined as dispersion of
vantage due to the small size and large surface area which
a hydrophobic drug or active ingredients in an inert hydro-
make laboratory and industrial handling of nanoparticles
philic carrier at solid state. This technique was developed
difficult in either liquid or dry forms.24 Newer biocompa-
in 1961 when Sekiguchi and Obi enhanced the rate and the
tible nanocomposites, such as nanoparticles and nanocap-
extent of absorption of sulfathiazole by using solid
sules, were developed and may overcome this problem.
dispersion.10 Since this year and up till now, the solubility
Many researchers tried to overcome the low solubility
of many drugs was improved.11–13 Solid dispersions can
problem of CC. But limited numbers of polymers were
improve the dissolution rate mainly by two ways: reducing
employed with limited selected polymer ratios. Some of
the size and, hence, increasing the surface area of the drug
them are unsuitable for industrial applications. In addition,
particle subjected to the dissolution medium.7 The second
no comparisons were made between the different techni-
is through improving the wettability of the particles under
ques which are very important for selecting the most
the influence of the hydrophilic polymer.5,14 In addition,
appropriate one. In addition, some studies carried out
solid dispersion may present drugs as supersaturated solu-
in vitro investigations only, while pharmacokinetic evalua-
tions which are considered to be metastable polymorphic
tions of the selected formulations were not touched.
form. Thus, it increases the solubility of the particles by
So, this work aimed to improve the dissolution velocity
presenting the drug in an amorphous form.14,15
of CC via preparation of solid dispersions using different
Another technique is the inclusion complexation with β-
polymers by solvent evaporation method and fusion
cyclodextrin (β-CD) or its derivatives; it increases the aqu-
method. Also, inclusion complexation with β-CD and
eous solubility of many water-insoluble drugs and increases
HP-β-CD was prepared by co-evaporation and evaluated
the bioavailability and the pharmacological effect.16–18 This
for industrial applications. Finally, nanoparticles of CC
increase in the pharmacological effect resulted in reducing
were prepared by solvent evaporation method using var-
the administered dose of the drug.7 Studies reported that the
ious polymers. The prepared samples were physicochemi-
release of enthalpy-rich water molecules from the CD’s
cally evaluated, and those that gave the highest dissolution
cavity is the driving force for the insertion of the guest
rate were further investigated for their bioavailability
molecule into the internal cavity.19 The attraction forces
enhancements.
between the guest molecule and CD may include hydrogen
bonds, hydrophobic interactions, van der Waals forces, and
charge-transfer interactions. For inhibiting polymorphic tran- Materials and Methods
sitions and crystallization rates during storage, hydroxypro- Materials
pyl-β-cyclodextrin (HP-β-CD) is useful. This is very Candesartan cilexetil is a gift sample provided by
important to maintain higher dissolution characteristics of Pharaonia Pharmaceuticals, Egypt. Polyvinylpyrrolidone
water-insoluble drugs with storage.20 Many evaluating para- K-30 (PVP K-30), polyvinylpyrrolidone K-90 (PVP
meters were employed to assess the quality of the formed K-90), sodium laurylsulphate (SLS), pitavastatin,

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polyethylene glycol (PEG), β-cyclodextrin (β-CD), and Table 1 Methods and Polymers Used in Preparation of Solid
hydroxypropyl-β-cyclodextrin (HP-β-CD) were purchased Dispersions, Inclusion Complexes and Nanoparticles of CC
from Sigma-Aldrich Chemical Co., USA. CC: Method CC:Carrier Sample
Carrier Ratio Code

Preparation of CC Solid Dispersion CC:PVP Solvent 1:1 F1

K-30 Evaporation
Solvent Evaporation Method
CC:PVP Method 1:2 F2
Specified amounts of CC with each polymer were dis-
K-30
solved in ethanol with continuous stirring. The solution CC:PVP 1:4 F3
was rotary-evaporated at 50ºC and 80 rpm using rotary K-30
evaporator (Heidolph, Germany). The dried mass was CC:PVP 1:1 F4
K-90
pulverized, sieved, and kept in desiccator pending further
CC:PVP 1:2 F5
studies.25 This method was carried out using PVP K-30 K-90
and PVP K-90 at 1:1, 1:2, and 1:4 drug:polymer weight CC:PVP 1:4 F6
ratios as presented in Table 1. K-90
CC:PEG Fusion 1:1 F7
4000 Method
Fusion Method
CC:PEG 1:2 F8
The solid dispersions of CC with PEGs with different
4000
weight ratios (1:1, 1:2, and 1:4) were prepared by the CC:PEG 1:4 F9
fusion method according to the method described by 4000
Dasharath et al.26 This method is more suitable for the CC:PEG 1:1 F10
6000
preparation of solid dispersions of the drug with PEGs.
CC:PEG 1:2 F11
Accurately weighed amount of each carrier was melted at
6000
55–63°C. To this, calculated amount of CC was mixed CC:PEG 1:4 F12
thoroughly for 20–30 s followed by quick cooling to 4°C. 6000
The dried mass was then pulverized, passed through 44- CC:PEG 1:1 F13
8000
mesh sieve, and stored in desiccators until used. This
CC:PEG 1:2 F14
process is carried out using PEG 4000, PEG 6000, and 8000
PEG 8000 with 1:1, 1:2, and 1:4 drug:polymer weight CC:PEG 1:4 F15
ratio as presented in Table 1. 8000
CC:β-CD Coevaporation 1:1M IC1
CC:HP β- Method 1:1M 1C2
Inclusion Complexation CD
Phase Solubility Studies of CC with β-CD and HP-β- PVP K30 Nanoprecipitation 10% S1
CD PVP K90 Method 10% S2
Phase solubility diagrams were carried out according to
the procedures that are first described by Higuchi and
Connor.27 Excess amounts of candesartan cilexetil were Slope
Kc ¼ (1)
placed into stoppered flasks. To the flasks, 20 mL of So ð1  SlopeÞ
distilled water containing different concentrations of β-
CD or HP-β-CD was added. To form complexes, these Preparation of Candesartan Cilexetil Inclusion
stoppered flasks were placed in a thermally controlled Complex (IC) Using Co-Evaporation Method
shaker at 25°C for 72 hrs. The samples were filtered This method was carried out as previously described by
using filter disc of 45 µm, the filtrates were analyzed several workers with modifications.28–30 Briefly, equimolar
spectrophotometrically at λmax of 256 nm against suitable quantities of β-CD or HP-β-CD and CC were dissolved in
blanks prepared in the same concentrations of β-CD or 100 mL of 50% ethanol in water with the aid of bath-
HP-β-CD. The solubility constant (Kc) was calculated sonicator. The solvent was evaporated at 55°C using rotary
using the following equation: evaporator. The obtained solid was pulverized, sieved

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through 44-mesh sieve, and stored in airtight containers. Characterization of the Prepared Samples
This process was carried out with 1:1 molar ratio of drug: Production Yield Determination
CDs as obtained from phase solubility diagram (Table 1). The production yield of the prepared samples was deter-
mined by dividing the last weight of the samples on the
Molecular Docking Study initial weight of the raw materials. Data represent the
To get deep insights into the consistency of CC-β-CD and mean of three determinations ± SEM.
CC-HP-β-CD inclusion complexes, molecular simula-
tions were performed using Molecular Operating Percent Drug Contents (%DC)
Environment (MOE) 2019.01 software (Chemical An accurately weighed 50 mg of the prepared samples
Computing Group, Montreal, QC, Canada). The crystal were placed in a 100 mL volumetric flask, completed to
structure of β-CD was downloaded from the Protein Data the volume with ethanol, and sonicated in an ultrasonic
Bank (PDB) (PDB code: 5E6Z).31 On the other hand, bath for 30 mins. The sample was filtered, and the drug
there is no crystal structure for HP-β-CD in PDB or contents were determined. The absorbance was measured
other structural databases. Therefore, the 3D structure of spectrophotometrically at 256 nm, as previously men-
HP-β-CD was built using the crystal structure of β-CD tioned, against a suitable blank. Percent drug contents
(PDB Code: 5E6Z) as a template as described before.32 were calculated from the following equation:
The 3D crystal structure of CC was downloaded from
crystallographic data found in the Cambridge structural Actual amount of drug
Percent drug contentð%DCÞ ¼
database (Reference Code: FETWEH).33 The applied Theoretical amount of drug
 100
docking method was the induced fit protocol. All other
parameters were left to their MOE default settings. (2)
Finally, the resulting docking conformations were
visually reviewed, and the pose with the lowest binding-
Particle Size and Surface Charge Determination
free energy for each type of the two CC-CD inclusion
The mean particle size and particle size distribution of CC
complexes was described.
nanoparticles were determined by Nanosizer (Quantachrome
CLIAS00, France) at ambient temperature. In order to get
Preparation of CC Nanoparticles appropriate concentrations for measuring the particle size,
Preparation of CC Nanoparticles (NP) Using samples were diluted with double-distilled water. Data are
Nanoprecipitation Method presented as mean of three determinations ± SEM. Zeta
Nanosuspensions were developed according to the nanopre- potential (ζ) of the prepared nanoparticles was measured by
cipitation method.34,35 In brief, each polymer (PVP K-30, the same apparatus. Results were calculated automatically
PVP K-90, PEG 8000, PEG 4000, or HPMC) was dissolved using Smoluchowski equation:
in aqueous solution containing SLS, as a stabilizer, by the aid
of a magnetic stirrer at 750 rpm (Table 1). Candesartan ζ ¼ Mh=e (3)
cilexetil was dissolved in the organic solvent, acetone, and
injected at a very slow rate (1 mL/min) by the help of syringe where ζ is the zeta potential, M is the mobility, e is the
to the antisolvent (aqueous solution, containing SLS and the dielectric constant, and h is the absolute viscosity of elec-
polymer) under high-speed mechanical agitation of 5000 rpm trolyte solution.
using Probe Sonicator (Sonica, Vibracell, USA) at ultrasonic
power input of 300 W for 8 mins time length to get the Transmittance Electron Microscope (TEM)
desired nanosuspension. To control the particle size, cooling In order to investigate the morphology of nanoparticles,
was maintained throughout the process using ice-water. The selected samples of nanoparticles were examined under
suspensions were kept under vacuum at 25°C for 2 hrs to TEM (JEM100 CX 11, Japan). The nanosuspension sam-
remove organic solvents. Finally, the system was dried by ple was diluted, and a drop was left for 30 into the copper
freeze dryer (Free-Zone 180, Labconco Corporation, mesh grids prior to staining process. Staining was carried
Missouri, USA) for further characterization.36 out using potassium phosphotungstate dye.37

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Physicochemical Studies Pharmacokinetic Studies

Powder X-Ray Diffraction (PXD) Among the tested samples, formula F6 (CC:PVP K-90 1:4)
The X-ray diffractogram was obtained using X-Ray apparatus was selected for the pharmacokinetic studies. This formula
(Joel XR diffractometer). The source of radiation was CuKα produced the highest dissolution rate; in addition, preparation
radiation operated at 35 KV and a current of 15 mA. The of CC as SD with PVP K-90 is simple, fast, and economic.
diffractograms were obtained using continuous mode with 2θ The pharmacokinetic studies were conducted on
values ranging from 4 to 100 at a rate of 2 degrees/min. healthy male New Zealand rabbits weighing 2.5–3 kg. In
order to avoid the effect of food, animals were fasted
Fourier Transform Infrared (FT-IR) Spectroscopy overnight with free access to water. Animals are allocated
FT-IR spectroscopy was carried out using potassium bro- into two groups, each consisting of 6 rabbits.
mide (KBr) method. Typically, 1–4 mg of each sample was
mixed with KBr and compressed into discs. Scanning was ● The first group received untreated CC in a dose level

carried out using NICOLET 6700 FT-IR spectrophot- of 10 mg/kg.

ometer over the range of 600–4000 Cm−1. A blank KBr ● The second group received formula F6 in a dose

pellet was used as a reference. equivalent to 10 mg/kg.

Differential Scanning Calorimetry (DSC) The doses were given orally and suspended in starch muci-
Thermal investigations of CC, polymer, physical mixture lage, as a single dose via feeding tubes. For blood sampling,
(PM) of CC with polymer, and different prepared samples a cannula was inserted into the marginal ear vein. Blood
were measured using differential scanning calorimetry samples (2.5 mL) were withdrawn periodically at specified
(PerkinElmer, 2-C, NY, USA). Procedures were done as time interval into heparinized tubes. Once withdrawn, the
samples were centrifuged at 5000 rpm and 4°C for 10
previously described by several workers.5,13 The sample
mins to separate plasma which is kept at −80°C pending
was heated from 30°C to 300°C at a rate of 10°C/min.
analysis. The guidelines followed for the welfare of the
animals are described in the National Institutes of Health
Dissolution Rate Studies Guide for the Care and Use of Laboratory Animals.39 All the
Dissolution of CC and the prepared samples was carried experiments were also approved by the commission on the
out according to USP40 using USP dissolution test appa- ethics of scientific research, faculty of pharmacy, Minia
ratus II (Hanson Research, California, USA).38 Briefly, University (Code number of the Project is 39/2019).
16 mg of raw CC, or its equivalent of the prepared sam-
ples, were placed in 900 mL 0.05 M phosphate buffer (pH Plasma Extraction
6.5) containing 0.35% polysorbate 20. The temperature Four hundred and fifty µL of plasma, 50 µL of I.S.
was maintained at 37°C ± 0.5°C with the paddles being (Pitavastatin), and 100 µL of (0.1%) formic acid were
kept rotating at 50 rpm. At specified time intervals, 5 mL added to glass tube and vortexed for 30 s. Then, 0.5 mL
samples were withdrawn, filtered, and assayed spectro- of extraction solvent (diethyl ether:dichloromethane, 4:1)
photometrically at 256 nm against a suitable blank. The was added and vortexed for 2 mins. Samples were centri-
withdrawn samples were replaced with the same volume fuged (3000 rpm for 10 mins), and the extraction solvent
of fresh dissolution medium maintained at the same tem- was evaporated at 40ºC and finally reconstituted by adding
perature. The experiment was carried out in triplicate, and specified volume of the mobile phase.
each point represents mean concentration ± SEM.
Analysis of Plasma Samples
Plasma samples were analyzed for the drug using Agilent
Statistical Analysis UHPLC unit (Agilent Corporation, MA, USA) with
All values were expressed as mean ± SEM. Kolmogorov– a ZORBAX Eclipse Plus C18 column (1.8 μm, 2.1 × 50
Smirnov. Tests were employed for estimating the normal- mm, I.D. Agilent Corporation, MA, USA) maintained at
ity of distribution. Statistical analysis was performed using 30°C. The mobile phase consisted of acetonitrile:distilled
one-way analysis of variance (ANOVA). The value of water (85:15). The flow rate was adjusted at 0.2 mL/min.
P less than 0.05 was considered statistically significant. The mass spectrometric detection was performed on

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Figure 2 Phase solubility diagram of CC/β-CD and CC/HP-β-CD in water at 250°C.

Agilent 6420 triple-quadrupole mass spectrometer improvement in the dissolution rate and is expected not
equipped with an electrospray ionization source (Agilent to significantly improve the bioavailability of CC.
Corporation, MA, USA) in a positive mode. Quantitative Statistical analysis confirmed this suggestion (P>0.05).
analysis was performed in the multiple reaction monitor- While HP-β-CD can theoretically improve the solubility
ing (MRM) mode. (P<0.001) but may also result in forming a very stable
complex, as discussed above, that may affect its liberation
Pharmacokinetics Analysis in blood and exertion of its pharmacological effect.
Data obtained from UHPLC experiments were utilized to
establish plasma concentrations-time curve. In addition,
Drug Contents and Particle Size Analysis
PK solver program was used to calculate the pharmacoki-
netic parameters.40 All data are presented as mean ± SD.
of the Prepared Nanoparticles
The production yields for the two samples (S1 and S2)
were 94.3% ± 2.6 and 95.2% ± 3.2. The drug contents for
Results and Discussion both samples were 99.4% ± 1.2 and 98.6% ± 1.8, respec-
Phase Solubility Studies tively. The average particle sizes of the two samples are
Phase solubility diagrams are shown in Figure 2. It was recorded in Table 2. It was noticed that the smallest
observed that the solubility of CC was increased as the particle size was achieved with formulations S1 and S2
concentration of complexing agents increased. The plot that were prepared using PVP K-30 and PVP K-90,
was found to be linear of A L type, indicating the forma- respectively, with acceptable PDI values. Other polymers
tion of complexes with stoichiometric ratio of 1:1. Slopes failed to produce nanosized particles of the drug (Data are
were found to be less than unity. Stability constants of the shown for both S1 and S2 only). It is needless to say that
drug (Kc) with β-CD and HP-β-CD showed values of the reduction in particle sizes may provide larger surface
0.1352 mM−1 and 3.201 mM−1, respectively. According area for rapid dissolution of the drug.41 Zeta potentials (ζ)
to literatures,21,22 being in the range of 0.1 and 2 mol.L−1, of S1 and S2, Figure 3, were found to be −43 (mV) and
β-CD may have industrial application, but the ability of the
complex to improve the solubility and the dissolution Table 2 Average Particle Size of CC Nanoparticles
remains limited, while HP-β-CD may form a very stable Sample No. Mean Particle Size (nm)± SD PDI
complex which is unsuitable for industrial application. In
S1 291.5 ± 20.19 0.418
other words, their abilities to improve the solubility, and
S2 238.9 ± 19.25 0. 320
hence the dissolution, varied. β-CD produced a limited

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Figure 3 Zeta potential (ζ) of the prepared nanoparticles: (A) S1 and (B) S2.

−23 (mV), respectively, reflecting the relative stability of potential at the imaginary surface of hydrodynamic shear.
the prepared nanoparticles as surface charges may prevent Studies demonstrated that values of zeta potential above
the aggregation and the agglomeration of the prepared ±30 mV were preferred to exert repulsive forces that
particles.23 It is important to mention that zeta potential prevent aggregation of particles.42 TEM images,
is not a direct measure of the surface charge; however, it Figure 4, showed uniform size of both S1 and S2 nano-
was calculated mathematically from the electrostatic particles that are approximately spherical in shape.

Figure 4 TEM images of the prepared nanoparticles: (A) S1 and (B) S2.

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Physicochemical Studies
Physicochemical characterizations were carried out for all
of the investigated polymers. The data was displayed for
polymers that produced higher dissolution rate only.
Among the tested PVP and PEG prepared samples, PVP
K-90 (1:4) and PEG 8000 (1:4) drug:polymer ratios were
selected for testing their physicochemical properties, as
these two samples produced higher dissolution rate than
other prepared PVPs and PEGs samples. In addition, HP-
β-CD gave higher dissolution rate than did β-CD. In case
of NP, the two prepared samples were physicochemically
investigated.

Powder X-Ray Diffraction (PXD) Patterns

X-ray diffraction patterns of CC, polymers, PM, and the
prepared samples are displayed in Figure 5. The X-ray
diffraction pattern of CC/PVP K-90 showed that CC exhi-
bits major crystalline peaks at 2θ values of ~10, 17, 20,
and 24 in addition to other smaller peaks, indicating the
high crystallinity of the drug. PVP K-90 diffractogram
showed an amorphous hump without any characteristic
peaks. PM diffractogram showed the major characteristic
peaks of the drug at their proper position but with lower
intensity, while the SD diffractograms showed complete
disappearance of CC peaks, suggesting that the drug did
not recrystallize during the preparation of SDs subsequent
to the evaporation of the solvent. These results suggested
Figure 5 X-ray diffraction patterns of (A) CC, (B) PVP-K90, (C) PM with PVP-
the presence of intermolecular interactions between the K90, (D) SD with PVP-K90, (E) PEG8000, (F) PM with PEG 8000, (G) SD with PEG
8000, (H) HP-β-CD, (I) PM with HP β-CD, (J) IC with HP β-CD, (K) PM with PVP-
functional groups of the PVP and the drug that resulted
K30, (L) nano with PVP-K30, (M) PM with PVP-K90, and (N) nanoparticles with
in the presence of CC in an amorphous form in the SDs. PVP-K90.

For CC/PEG 8000, PEG 8000 diffractogram showed major

crystalline peaks at 2θ values of ~19 and 27. The solid
dispersion diffractogram differed from its corresponding Fourier Transforms Infrared (FT-IR) Spectroscopy
PM, and some of the characteristic peaks of the drug either In order to investigate the intermolecular interactions, FT-IR
disappeared or appeared with lower intensity, indicating spectra for CC, polymers, and different samples were stu-
the presence of the drug in less crystalline state within the died. The PMs were included for comparisons with the SDs.
solid dispersion. Results are shown in Figure 6. Candesartan cilexetil dis-
In case of inclusion complexes, HP-β-CD diffracto- played a characteristic peak for the N-H stretching vibration
gram showed that an amorphous hump indicated an amor- at 3406.9 cm−1 and a band with strong intensity at
phous structure of HP-β-CD. In the ICs, the peaks 1752.5 cm−1 indicative of the C=O stretching of the ester
intensities of the drug were markedly decreased, indicating group. The methyl group, CH3, showed a peak at
partial inclusion of the drug within the cavity of the CDs. 2940.1 cm−143 For PVP K-90 system, FT-IR spectrum of
Regarding the prepared nanoparticles, NP diffracto- SD displayed differences in the shape and position of the
gram showed complete disappearance of the major peaks above-mentioned bands. The presence of hydrogen bonding
of drug in both samples, indicating the presence of CC in is indicated from band shifts associated with the potential
the amorphous form within the prepared NP. hydrogen bond donating group N-H on CC and the strong

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IR spectrum of CC nanoparticles with PVP K-90 was

discussed above.

Differential Scanning Calorimetry (DSC)

DSC thermograms of CC, polymers, PM, and the prepared
samples are displayed in Figure 7. It could be observed from
Figure 7A that CC has a sharp endothermic peak at 171ºC
corresponding to its melting point followed by an exother-
mal peak, may be ascribed to decomposition of the drug.
Concerning PVP K-90 thermogram, Figure 7B shows
a broad endotherm over the temperature range from 80°C
to 115ºC, which attributed to the loss of residual moisture
present in PVP K-90.43 DSC thermogram of PM showed
a small shift of the drug peak that disappeared in SD con-
firming the presence of interaction between the drug and the

Figure 6 FT-IR of (A) CC, (B) PVP-K90, (C) PM with PVP-K90, (D) SD with PVP-
K90, (E) PEG8000, (F) PM with PEG 8000, (G) SD with PEG 8000, (H) HP-β-CD,
(I) PM with HP β-CD, (J) IC with HP β-CD, (K) PM with PVP-K30, (L) Nano with
PVP-K30, (M) PM with PVP-K90, and (N) nanoparticles with PVP-K90.

hydrogen bonding accepting group –OH on polymer carrier.

The PM showed the peaks of CC in their proper wave
number, without significant band shifts. FT-IR spectrum of
PEG 8000 showed a characteristic band at 3426 cm−1 due
to –OH group, and another band appeared at 2888 cm−1 due
to -CH. All bands of CC appear in PM at their proper
position. However, a change in their shapes and positions
occurs in SD suggesting the formation of hydrogen bond
between –OH of PEG and C=O group of CC as indicated by
broad band in the region 3200–3600 cm−1.
IR spectrum of CD was characterized by intense bands
at 3300–3500 cm−1 due to –OH groups of CD. In addition,
two bands appeared at 2925 cm−1 and 1640 cm−1 due to -
CH and C=O, respectively.44 In contrary to PM, IR spec-
trum of the prepared samples indicated that most of the
absorption bands in the region 2500–3500 cm−1 were
masked by the bands of CDs, with complete disappearance
of CC bands in this region. The broad band at
Figure 7 DSC thermograms of (A) CC, (B) PVP-K90, (C) PM with PVP-K90, (D)
3000–3500 cm−1 may indicate the possibility of hydrogen SD with PVP-K90, (E) PEG8000, (F) PM with PEG 8000, (G) SD with PEG 8000,
bonding of carbonyl C=O group of CC with –OH of HP-β- (H) HP-β-CD, (I) PM with HP β-CD, (J) IC with HP β-CD, (K) PM with PVP-K30,
(L) Nano with PVP-K30, (M) PM with PVP-K90, and (N) nanoparticles with PVP-
CD. K90.

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polymer. With regard to CC/PEG 8000 system, Figure 7E, molecular level, within cyclodextrins hydrophobic cav-
PEG showed a sharp endothermic peak at 65ºC correspond- ity and their hydrophilic edges.45 Therefore, molecular
ing to its melting point. The DSC thermograms of both PM docking simulation of CC-β-CD and CC-HP-β-CD com-
and SD showed disappearance of the peak of CC that may plexes was performed via MOE program. The molecular
suggest possible solubility of CC within PEG. Figure 7H docking results are summarized in Figure 8. The binding
(HP-β-CD) showed a broad endotherm in the region of energies calculated for CC-β-CD and CC-HP-β-CD
70–120 ºC that could be attributed to the release of water inclusion complexes were −8.4 kcal/mol and −9.2 kcal/
molecules from the cavity of CD. While DSC thermogram mol, respectively. The size of HP-β-CD cavity is larger
of PM showed the two characteristic peaks for both CC and than β-CD cavity, because it has an extra extension
polymer at their proper position, the DSC thermogram of IC result from the hydroxypropyl replacement in compari-
showed disappearance of CC band, suggesting the formation son with β-CD. As depicted in Figure 8A, the cavity
of inclusion complex between CC and polymer. size of β-CD was small for hosting CC with only one
DSC thermogram of nanoparticles, Figure 7K and N, hydrophobic (CH-) interaction resulting in a less stable
showed a small shift in the position of CC peak and complex with binding constant of −8.4 kcal/mol
decrease in its intensity in the PM that nearly disappeared (Figure 8C). Conversely, the candesartan moiety was
in the prepared nanoparticles. completely buried in HP-β-CD (Figure 8B) in addition
to electrostatic interaction (H-bonding) between carbox-
Molecular Docking Study ylate group (C=O) of CC and the hydroxyl (OH) group
Molecular modeling is one of the finest techniques to of the 2-hydroxypropyl radical of HP-β-CD (Figure 8D).
calculate the drug orientations and interactions, at the This interaction results in a very stable complex with

Figure 8 The 3D structures of CC and two cyclodextrins (β-CD and HP-β-CD), showing the predicted orientations of CC within the hydrophobic cavity of β-CD (A) and
HP-β-CD (B) from the side view as well as its binding interactions with the hydrophilic edges of β-CD (C) and HP-β-CD (D) as stick molecular depiction. Hydrogen bonds
and hydrophobic interactions are demonstrated as black and red dashed lines, respectively.

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a binding energy of −9.2 kcal/mol. These results allied complexes, approve the higher affinity of CC towards
well with FT-IR and DSC results (Figures 6 and 7), HP-β-CD rather than β-CD. This calculation associated
where a band at 3000–3500 cm−1 appeared more broad well with the experimental stability constants values of
and the CC melting peak disappeared with the processed CC with β-CD and HP-β-CD.
mixture of CC and HP-β-CD, demonstrating a strong
physicochemical interaction. Similar results of the CC Dissolution Rate Studies
docking pose with HP-β-CD have been reported Figure 9A displays the dissolution rate of CC/PVP K-30
recently.46 To sum up, the differences observed in the system. Both 1:1 and 1:2 CC:polymer weight ratio did not
binding energy, as well as the number and the type of produce significant increases in the dissolution rate
interactions between CC-β-CD and CC-HP-β-CD (P>0.05). However, 1:4 drug:polymer ratio produced

Figure 9 Issolution rate of (A) CC/PVP-K30, (B) CC/PVP-K90, (C) CC/PEG4000, (D) CC/PEG6000, (E) CC/PEG8000, (F) CC/CD, and (G) CC/NP. Data represent mean
cumulative % released ± SEM.

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Figure 10 UPLC MS/MS spectrum of Candesartan and the I.S. (Pitavatatin) showing the retention time of CC and I.S.

a significant (P<0.01) increase in the dissolution velocity. Pharmacokinetic Studies

Regarding PVP K-90, Figure 9B, the polymer increased the Figure 10 shows UPLC mass spectra for the solid disper-
dissolution rate significantly even at 1:1 ratio. Nearly 95% of sions of the drug obtained after oral administration of CC.
the drug was dissolved by the end of the first hour of the The retention times were 2.1 mins for the internal standard
experiment. This could be attributed to the formation of (Pitavastatin) and 2.9 min for CC.
hydrogen bonding and the presence of the drug in less Candesartan plasma concentration versus time data
crystalline or amorphous form, as illustrated by the physi- after oral administration of 20 mg of CC as SD could be
cochemical investigations. Regarding PEGs, PEG 8000 best described by a one-compartment model with first-
increased the dissolution rate insignificantly (P>0.05) at order absorption and elimination. The results obtained
1:1 and 1:2 drug:polymer ratios, Figure 9E. PEG 4000 and are reported in Table 3 and depicted in Figure 11, and
PEG 6000 produced significant increases in dissolution rate the AUC0-∞ obtained for SD was 342.06 ± 13.57 ng/
at the same ratios (P<0.05), Figure 9C and D. All PEGs mL·h which is approximately twofold and significantly
produced significant differences (P<0.01) at 1:4 drug:poly-
mer ratios. The improvement of dissolution rate in SD could
be generally ascribed to higher wettability, and dispersibility Table 3 Pharmacokinetic Parameters of Candesartan in Plasma
of Rabbit After Oral Administration of 20 Mg of CC as a Solid
of drug with hydrophilic carrier resulted in greater wetting
Dispersion and CC Alone.
and increased surface available for dissolution.36
Pharmacokinetic Unit CC (SDs) CC Alone
Insignificant increase in the dissolution rate of CC
Parameter
was produced by β-CD, while HP-β-CD improved the
Cmax ng/mL 135.32 ± 44.22 ± 1.35
dissolution velocity in a significant manner (P<0.05),
2.11
Figure 9F. Results of dissolution with cyclodextrins are
Tmax h 1.69 ± 0.13 1.75 ± 0.17
somewhat expected. β-CD poorly interacted with the AUC0-inf ng/ 342.82 ± 159.32 ±
drug as indicated by physicochemical and docking mL·h 13.57 12.74
studies. A ng/mL 3196 ± 1570 ±
26.66 35.38
The dissolution rate of CC in the nanoparticles was
K h−1 0.545 ± 0.08 0.555 ± 0.04
significantly (P<0.001) increased. After 2 hrs, ~63% and
Ka h−1 0.579 ± 0.04 0.589 ± 0.06
~77% of the drug were dissolved from S1 and S2, respec- AUMC0-inf ng/ 1217.8 ± 570.23 ±
tively, Figure 9G. The reductions in particle size combined mL·h2 25.46 19.11
with the interaction between CC and the polymers may MRT h 3.51 ± 0.14 3.49 ± 0.18

explain this higher dissolution rate. Data are presented as mean ± SEM.

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Figure 11 Concentration-time profiles of CC alone and in SDs with PVP K-90 (data displayed±SEM).

higher than that obtained by CC alone (159.93 ± 12.74 Conclusions

ng/mL·h). These results could be attributed to the higher It was concluded that the dissolution rate of CC was
dissolution rate of the SD and the lower solubility of significantly improved when formulated as SDs.
untreated CC. This higher AUC is combined with Physicochemical evaluations revealed the presence of
a pronounced, statistically significant (P>0.01) elevation interaction, may be hydrogen bonding, between the
in Cmax and slight lowering of Tmax values. Cmax of the drug and the investigated polymers. Animal studies con-
prepared SD was 135.32 ± 2.11 ng/mL which is three firmed that the bioavailability of CC was significantly
times higher than that produced by CC alone. The area improved when formulated as SDs with PVP K-90 with
under first moment curve (AUMC) is ordinarily obtained 1:4 drug:polymer ratio.
by plotting plasma concentration multiplied by time
against time of sampling. So it is not surprising that
AUMC of the SD (1217.8 ± 25.46 ng/mL·h2) was
Data Sharing Statement
All the data supporting the results of this study are
numerically and statistically higher than the drug alone
included in the article.
(570.23 ± 19.11 ng/mL·h2). Mean residence time, in
turn, remained nearly constant. It could be also noticed
that the solid dispersions resulted in faster absorption Disclosure
rate than the drug alone as illustrated from the figure, The authors report no conflicts of interest in this work.
while the elimination rate constant (K) remained
unchanged in both samples. The enhancement of the References
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