International Journal of Biological Macromolecules 131 (2019) 879–885

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International Journal of Biological Macromolecules

journal homepage: http://www.elsevier.com/locate/ijbiomac

Chitosan-telmisartan polymeric cocrystals for improving oral absorption:

In vitro and in vivo evaluation
Mani Ganesh a,⁎, Udhumansha Ubaidulla b, Grace Rathnam b, Hyun Tae Jang a,⁎
a
Department of Chemical Engineering, Hanseo University, 360 Daegok-ri, Seosan-si 356 706, Chungcheongnam-do, South Korea
b
Department of Pharmaceutics, C.L. Baid Metha College of Pharmacy, Chennai, India

a r t i c l e i n f o a b s t r a c t

Article history: This study describes the development of polymeric cocrystals of chitosan-telmisartan (TEL) to improve the oral
Received 27 December 2018 bioavailability of TEL, which has poor oral solubility and bioavailability. The polymeric cocrystal was prepared
Received in revised form 12 March 2019 using chitosan a biopolymer with the aid of sodium citrate as a salting-out agent. The cocrystals were character-
Accepted 21 March 2019
ized by FT-IR spectroscopy, scanning electron microscopy, differential scanning calorimeteri (DSC), thermogravi-
Available online 22 March 2019
metric analysis (TGA), and powder X-ray diffraction (PXRD). The improved solubility of TEL was observed with
Keywords:
cocrystals as compared to that of pure drug in solubility studies with phosphate buffer (pH 7.4). The in vivo
Telmisartan pharmacokinetics properties of cocrystal were studied by an animal model using rats after a single dose oral ad-
Chitosan ministration. The results showed an increased plasma drug concentration (Cmax) of 1.47, μg/ml for cocrystals
Polymeric cocrystals when compared to pure TEL with 0.96 μg/ml with one-fold increased bioavailability (F%) that is, the cocrystals
Oral absortion increases the solubility of the drug and the paracellular drug absorption by tight junction modulation. Further
Bioavailability the elimination constant Kel resulted with higher value of about 0.0085 h−1 when compared to pure drug
with0.0048 h−1 along with improved AUC (14.62 μg/ml).
© 2019 Elsevier B.V. All rights reserved.

1. Introduction in vivo pharmacokinetics [16]. Mutalik et al. reported that aceclofenac-

Dissolution of a drug is considered to be the rate-determining step
for oral absorption of the poorly water-soluble drugs. Selection of a
method to increase solubility is the key to achieve good oral bioavail-
ability, reduce frequency of dosing, have better patient compliance,
and lower the cost of production. Many techniques have been reported
to improve drug dissolution, such as particle-size reduction, salt forma-
tion, solid dispersion, use of a surfactant, and complexation [1–5]. Re-
cently, pharmaceutical cocrystals have received much attention in the
pharmaceutical industry for improving the bioavailability of poorly
water-soluble drugs, especially for these neutral compounds or those
having weakly ionizable groups. Moreover, many reports revealed that
cocrystals could improve the physicochemical properties of the drug,
such as melting point, solubility, dissolution, and stability [6–15].
Pharmaceutical cocrystal is prepared based on the supramolecular
chemistry; i.e., drug and crystal former are combined to form cocrystals
by means of intermolecular interactions, mainly hydrogen bonds and
van der Waals forces. Many API–coformer combinations in orally ad-
ministrated pharmaceutical cocrystals are considered to dissociate
upon dissolution and dilution in the gastrointestinal tract, as suggested
by studies on the relationship between cocrystal in vitro dissolution and
⁎ Corresponding authors.
E-mail addresses: chemgans@gmail.com (M. Ganesh), htjang@hanseo.ac.kr (H.T. Jang).
chitosan crystals could improve in vitro dissolution and in vivo pharma-
cokinetic properties of drugs. The coformer chitosan (CS) is “generally
recognized as safe” (GRAS) by the US FDA and is widely regarded as a
biocompatible, nontoxic, and non-allergenic material that is, therefore,
highly suitable for use in medical and pharmaceutical applications
[17–19].
Telmisartan (4′-{[4-Methyl-6-(1-methyl-2-benzimidazolyl)-2-
propyl-1-benzimidazolyl] methyl}-2-biphenylcarboxylic acid) has
been used for treatment of hypertension that belongs to the BCS class
II drugs [20,21]. A major problem with this drug is its low solubility
in biological fluids, which results in poor bioavailability after oral ad-
ministration. The solubility of TEL in aqueous medium is very low:
0.078 mg/ml in water. Absolute bioavailability of the TEL was 42–58%.
Poor solubility of TEL leads to poor dissolution and hence it shows
variations in bioavailability [22]. For improving the solubility and
bioavailability of TEL, various formulations have been reported, such
as immediate release tablets [23], nanoparticles [24,25], nano self-
emulsifying drug-delivery systems [26], amorphous formulations [27],
solid dispersions [28,29], and alkalizers [30]. Lin et al. revealed that
TEL–chitosan solid dispersions are formed by electrostatic interactions
between TEL and CS caused by the anionic nature of the drug and the
strong positive charge of the polymer [29]. Cocrystals using a crystal-
engineering approach is one technique used to improve the dissolution
and bioavailability of poorly soluble drugs. The ionizable functionalities

https://doi.org/10.1016/j.ijbiomac.2019.03.141
0141-8130/© 2019 Elsevier B.V. All rights reserved.
880 M. Ganesh et al. / International Journal of Biological Macromolecules 131 (2019) 879–885
of TEL present possibilities for co-crystallization by hydrogen bonding.
There have been very few reports of studies that used this approach,
using various [31–34] acids like citric, gallic, or saccharin as co-
formers. Using weak acids as co-formers will also cause some problem,
such as poor dissociation, gastric irritation, and alkalizing the microen-
vironment of the intestinal lumen. Chitosan is the best biodegradable
co-former that can increases the solubility of poorly soluble drugs,
as stated earlier [17–19,34,35]. This has prompted us to explore the
possibility of developing TEL-CS cocrystals by a one-step process using
a citrate ion without any toxic cross linking agents, and to study their
potential for improving dissolution rate and physicochemical proper-
ties. Our objective is to develop a TEL cocrystal using chitosan to
increase the solubility and dissolution rate of TEL by preparing its
cocrystals using citrate-ion cross linking and to carry out physicochem-
ical characterization of the optimal formulation by using infrared
spectroscopy, XRD, DSC, and surface morphology, as well as an in vitro
drug release and in vivo oral absorption study.
2. Materials and methods
2.1. Manterials
Telmisartan (TEL) and chitosan (low molecular weight, N 85%
deacetylated, poly(d-glucosamine)) were procured from TCI Chemical,
Japan, and glacial acetic acid was purchased from Dae Jung Chemicals
and Metals, Korea. All other chemical used herein were of commercial
grade unless otherwise specified in the respective areas.
2.2. Preparation of cocrystals
Drug and chitosan macromolecular cocrystals were prepared as re-
ported in our earlier research on aceclofenac chitosan cocrystals
[18,19], but with a little modification. In the typical protocol the drug
was separately dissolved in methanol and the chitosan was dissolved
in 1% acetic acid (10 ml). Then the solutions of drug and polymer
were simultaneously added drop wise to 1% sodium citrate solution
(citrate common ion) that acts as a salting-out agent with stirring
using high-speed homogenizer (Daihan Scientific,Korea) at a rate of
1000 rpm. The cocrystals were formed while the addition began. After
the complete addition of the two solutions, the stirring was continued
for another 30 min to evaporate the methanol; the resultant was then
filtered through Whatman filter paper (No. 1) and dried under vacuum
at 45 °C overnight. The resulted powder was further subjected to sifting
using a sieve with mesh no #40. Different formulations were prepared
using a fixed drug concentration with different concentrations of
polymer, as listed in Table.1. The formulations obtained were labeled
TCC-1 (Temisartan chitosan cocrystals), and TCC-2 to TCC-8 in terms
of their drug-polymer weight ratios.
2.3. Characterizations
2.3.1. XRD
Changes in the crystalline structure of TEL before and after formula-
tion were studied using Powder X-ray diffraction. The required quantity
of drug and formulations were placed in the XRD sample holder then
scanned using Rigaku Miniflex X-ray diffractometer with Cu Kα radia-
tion and operated at 40 kV and 30 mA (l = 1.54 (Å); a 2θ range of
Table 1
Composition of various co-crystals formulation.
Component TCC-1
1. TEL(mg) in 10 ml water 40
2. Chitosan (mg) in 10 Acetic acid (1%) 40
3. Sodium citrate (1%, ml) 100
5–45° with a 0.02° step size and a 1 s step time was fixed as the param-
eter for retrieving the XRD.
2.3.2. Scanning electron microscopy (SEM)
To study the morphology of the pure drug and cocrystal formulation,
SEM analysis was performed. Samples were dusted over the double-
sided carbon adhesive tape, placed over the alluminium stub, and
coated with gold by a plasma sputter coater (Cressington, Sputter
Coater-108 auto, Korea). The images were recorded using a scanning
electron microscope (Jeol-JSM 5600, Japan).
2.3.3. FT-IR
FT-IR spectral analysis of TEL and various drug-chitosan cocrystal
formulations were recorded using a Thermoscientific Nicolet IR 200
spectrometer by KBR pressed-pellet technique. The KBr pellets were
made by mixing required quantities of pure drug (TEL), chitosan, and
various formulations (TCC-1 to TCC-8) with 100 mg of dried KBr and
pressed into pellets using a KBr pellet press. Then each pellet was
scanned 40 times at 4 cm−1 resolution over the wavenumber range of
4000–400 cm−1.
2.3.4. DSC
To study the changes in the crystal structure during the cocrystal
formulation, DSC analysis was done. A Scinco DSC N 650 differential
scanning calorimeter was used to record the DSC traces of the TEL
pure and cocrystals. The samples were loaded into the aluminum pan
of the DSC instrument and scanned at a heating rate of 10 °C/min
under a helium environment by purging helium at 40 ml/min.
2.3.5. TGA
Pure drug and various cocrystal samples were loaded (ca. 10 mg)
into the platinum sample pan of the Scinco N-1000 thermogravimeter
unit, and the temperature was programmed to reach 600 °C at a heating
rate of 10 °C/min in a nitrogen atmosphere.
2.4. In vitro drug release
The in vitro release of TEL and cocrystals was tested in a USP XXII dis-
solution apparatus. An equivalent weight of cocrystals containing 40 mg
of TEL was placed separately in 900 ml of intestine fluid (pH 7.4) main-
tained at 37 ± 0.5 °C and stirred at 50 rpm. About 5 ml aliquots of was
collected at regular time intervals, and the same amount of fresh
dissolution medium was replaced into a dissolution vessel to maintain
the sink condition throughout the experiment. The aliquots were fil-
tered, further diluted suitably, and estimated spectrophotometrically
at 296 nm.
2.5. In vivo evaluation
The study protocol was approved by the Research and Ethical Com-
mittee of C.L. Baid Metha College of Pharmacy, India (Ethical clearance
no: 17/321/PO/Re/S/01/CPCSEA). For in vivo studies, healthy albino
rats of either sex, weighing 200 ± 20 g, were used. The rats were
divided into three groups, each consisting of six rats. Group 1 animals
were administered the pure drug, Group 2 animals received an
optimized formulation (TCC-6), and Group 3 animals were treated as
the control. The rats were kept in individual cage for seven days prior
to the study in the departmental animal house for acclimation. The
TCC-2 TCC-3 TCC-4 TCC-5 TCC-6 TCC-7 TCC-8
40 40 40 40 40 40 40
80 120 160 200 240 280 320
100 100 100 100 100 100 100
 M. Ganesh et al. / International Journal of Biological Macromolecules 131 (2019) 879–885
cocrystals were administered to the rats through the feeding tube
(oral gavage) (1 mg/kg., p.o). The blood samples were collected from
the tail vein of rats in centrifuge tubes (containing sodium heparin as
an anti-coagulant). The blood samples were collected at 0.5, 1, 1.5, 2,
3, 4, and 6 h for the pure drug and cocrystals. The collected blood
samples were centrifuged at 3500 rpm for 15 min to separate the
plasma for drug-content analysis. The plasma was separated carefully
and stored at 2–10 °C. The plasma samples were analyzed, using a
reversed-phase high-performance liquid chromatography (HPLC) with
reference to procedure portrayed by Shen et al. [36] as follows about
0.5 ml of plasma sample was made acidic with 1 M HCl. The solutions
were violently vortexed with 4 ml of ethyl acetate for 5 min. Then
they were centrifuged at 4000 g for 10 min and the organic phase was
transferred to a clean tube and evaporated to dryness at 50 °C with
the aid of a gentle stream of N2 and analyzed by HPLC.
2.6. In vivo pharmacokinetic analysis
The most common pharmacokinetic parameters, such as peak plasma
concentration (Cmax), time to reach maximum plasma concentration
(Tmax), and total area under the plasma concentration-time curve
(AUC0–∞), were measured from the plasma-concentration time profile
of the cocrystal and pure drug. The peak plasma concentration (Cmax)
and time of its occurrence (Tmax) were calculated directly from each
plasma concentration. The AUC of cocrystal and pure drug were calcu-
lated by trapezoidal method. The elimination rate constant (Kel) of
cocrystals and pure drug was calculated using Eq. (1). Relative bioavail-
ability (%) of TEL cocrystal was calculated using equation (Eq. (2)).
Kel ¼ Slope=0:203
AUCtest Doseref
%Relative bio−availability ¼   10
AUCref Dosetest
2.7. Statistical analysis
All measured data were expressed as mean ± standard deviation
(S.D.), and were analyzed using BioStat version 2009 for Windows
software.
3. Results and discussions
3.1. XRD
The XRD results of pure drug TEL and its cocrystal formulation are
shown in Fig. 1. The major characteristic diffraction peaks for pure TEL
Fig. 1. PXRD properties of Pure and chitosan cocrystals of telmisartan.
881
were observed at 2θ of 6.9°,10.5°, 11.84°, 12.0°, 12.4°, 14.16°, 15°,
18.6°, 23.78°, 25°, 2.9° and 31.0°, 33.74°, 34.14°, and 40.43° [31,32].
The major diffraction peaks from 5 to 40 (2θ), such as 6.9°, 10.5°,
11.84°, 12.0, 12.4°, 14.16°, 15°, 18.6°, and 23.7° were also observed
with formulations like TCC-1 to TCC-4, but with decreased intensity.
These results proved that the drug-polymer ratio of until 1:4 (wt) has
less effect on the crystalline structure of TEL, but on further increase in
polymer weight, the diffraction intensities were reduced gradually
and the amorphous phase slowly appeared because of the increased
polymer concentration, the polymer deposits masks the diffraction or
reaching of X-rays to the planes of TEL because of the formation of
thick gel like layer over the crystals. In case of unit cell structure
the PXRD patterns of the pure TEL crystals gives a triclinic symmetry
(a = 14.679 Å,b = 9.689 Å, c = 6.695, α = 95.793, β = 93.125 and
γ = 94.855) with P1 space group (using EXPO2014 crystal structure so-
lution,freeware from http://www.ba.ic.cnr.it/softwareic/expo/). But in
case of polymer drug cocrystals the polymer disrupted the crystalline
structure of TEL and forms new amorphous structure by hydrogen
bonding between carboxyl –C=O TEL with –NH (free amino or
amide) of the chitosan and forming newer synthons as explained earlier
studies [34]. This further supported by the following FTIR results and
DSC. Crystal structure elucidation for the amorphous co-crystal with
available PXRD data is impracticable and hence, the results from FT-IR
study were only used to determine the possible interaction between
the drug and polymer. The similar interaction was also reported with
TEL cocrystals with atenolol and irbesartan [34].
3.2. FT-IR
ð1Þ Fig. 2 shows the FT-IR spectrum of pure TEL and it cocrystal formula-
tions. The FT-IR spectrum of the pure drug is shown in Fig. 1 (TEL), in
which the vibrational band at around 3450 cm−1 was attributed to
ð2Þ
O\\H stretching of \\COOH; the aromatic C\\H stretching vibrations
were observed near 2900 cm−1, \\OH bending and \\C_O stretching
of\\COOH acid at 1385 cm- 1, and C_C ring vibrations of the aromatic
nucleus near 1600 cm−1. Further, the bands near 1350–1210 cm−1
were assigned to the C\\N stretching of the imidazole ring of TEL. The
pure chitosan (Supplementary Fig. S1) had predominant peaks at
3750 and 3000 cm−1 for the stretching vibrations of OH that was
merged with N\\H stretching of the glucosamine moiety. The vibra-
tional band near 2850 cm−1 was attributed to the CH bond of CH2 of
the sugar moiety. In addition, the methylene bending was observed
near 1375 cm−1 [18,19].
For the formulation TCC-1, the major peaks of TEL in the fingerprint
region were clearly visible. The intensity of the transmittance band
Fig. 2. FTIR spectrum of Pure drug and chitosan- telmisartan cocrystals.
882 M. Ganesh et al. / International Journal of Biological Macromolecules 131 (2019) 879–885
caused by the aromatic –CH stretching vibrations near 2900 cm−1 were
reduced, but there was a broad band caused by –OH vibration by water
molecules of the solvent, and –OH and –NH stretching of TEL were
observed from 2750 to 3600 cm−1 with little shifting from its original
position and broaden when compared to pure TEL. Further the – C_O
stretching of – COOH acid at 1385 cm- 1 and the vibrational bands
near 1350–1210 cm−1 for C\\N stretching of the imidazole ring of TEL
also shifted/disappeared that proves the participation hydrogen bond-
ing during the co-crystallization of newer synthons with (O\\H⋯O,
O\\H⋯N, N\\H⋯O, and N\\H⋯N) interaction of TEL and chitosan to
form multi component cocrystals through (1) Non-covalent forces like
acid–amide, alcohol-amide, acid–acid, and amide–amide interactions
that are usually of hydrogen bonding nature that holds the drug and
conformer together in the cocrystal. Likewise, the percentage transmit-
tance of the aromatic-ring vibration caused by C_C of the aromatic
functionality at around 1600–1800 cm−1 was also reduced that was in
observed in all formulations, but the intensity was reduced by increas-
ing the ratio of polymer. For the formulations TCC-5-TCC-7, the band
at 2900 cm−1 of the aromatic \\CH vibration is not visible, because
of over depositing of chitosan over the drug which makes the TEL
complete amorphous crystals instead of ionic crystals. Similar type of
interaction was also reported earlier with cocrystals of TEL with other
co-formers [34,35].
3.3. Scanning electron microscopy
The scanning electron microscopic images of the pure drug TEM and
the formulations are depicted in Fig. 3. Pure TEL shows small, needle-
like, pure pristine crystals, whereas the TCC-1 to TCC-4 cocrystals
was soft with rough morphological surfaces consisting pores in their
Fig. 3. SEM morphological characters of pure drug and chitosan- telmisartan cocrystals.
structure under low magnification (figure not shown). At high magnifi-
cation, the (X5000) crystals of TEL with deposits of polymer were seen
clearly in TCC-1 and TCC-2, but the number and size of crystals were re-
duced in TCC-3 and TCC-4. Even though the number of crystals was re-
duced, their morphology was impervious. The pores over the surface of
the cocrystals may support the imbibitions of the solvent and biological
fluids and thereby increase the solubility and bioavailability of TEL as
expected. This crystalline character was supported by the XRD data, as
discussed earlier. For the TCC-5 to TCC-8 formulations, the TEL crystals
were not visible; only the polymer surface was observed with some
small protrusions caused by crystals inside the surface.
3.4. Differential scanning calorimetric (DSC)
Fig. 4 is the DSC thermogram of TEL and cocrystal formulations. The
DSC of pure TEL shows a sharp melting endotherm peak that stretches
from 261 °C to 276 °C, with a peak maximum at 270.5 °C [37], equivalent
to the melting endothermic range of pure TEL. For the cocrystal formu-
lations TCC-1 andTCC-2, the endothermic peak for TEL shifted slightly
toward a lower value (266 °C), due to the changes in the crystalline
geometry of TEL caused by the deposition of the chitosan over the TEL
by the hydrogen-bonded interaction of the –COOH and –NH(imidazole)
group of TEL with the free amino or amide group of chitosan. However,
the peak appearance clearly shows that there was no ionic interaction
that formed with other TEL cocrystals in earlier studies [33,34].
In the formulations from TCC-3 to TCC-8, the endothermic peak
intensity was gradually get reduced and unidentifiable from TCC-6
to TCC-8, which shows the changing of the crystalline structure to
amorphosization of TEL crystals caused by the over depositing of
chitosan.
 M. Ganesh et al. / International Journal of Biological Macromolecules 131 (2019) 879–885
Fig. 4. DSC traces of pure drug and chitosan- telmisartan cocrystals.
3.5. TGA
The results of the thermogravimetric analysis are depicted in Fig. 5.
in which the TGA of pure TEL shows a two-step degradation profile.
The first degradation of TEL starts near 265 °C, as is supported by the
DSC results as earlier discussed; that is, it starts to melt at 270 °C. After
265 °C to 410 °C, there is a huge weight loss of around 50%; after that,
the second weight loss begins and end near 650 °C, with around a 43%
weight loss, which is similar with earlier reports [37]. However, for
TCC-1 and TCC-2, the first weight loss started a little earlier than that
of pure TEL, at 195 °C, and ends before 350 °C; the second weight loss
was similar with TEL but the thermogram ended before 600 °C. These
results prove that the chitosan deposit over the crystals affect the crystal
structure of the TEL and convert the crystals into amorphous powder
gradually from TCC-1–TCC-8.
3.6. In vitro drug-release study
All the formulations (TCC-1 to TCC-8) of the prepared cocrystals of
TEL were subjected to in vitro release studies, which were carried out
using a USP dissolution apparatus type II using pH 7.4 buffer for 2 h.
The drug release increased when the concentration of chitosan in-
creased (Fig. 6). Chitosan is a well-known biocompatible co-former
used to prepare cocrystals that increases the dissolution rate of TEL by
increasing its wettability by its hydrophilic nature there by altering
Fig. 5. TGA traces of pure drug and chitosan- telmisartan cocrystals.
883
Fig. 6. In-vitro drug release profile of pure drug and cocrystal formulations.
the surface morphology of the drug, and reducing particle size. The de-
positing of the chitosan polymer over the drug particles was higher and
stronger when associated with sodium citrate. The reaction of chitosan
with multivalent anion sodium citrate leads to the formation of bridges
between the polymeric chains, which results in efficient deposition of
chitosan by forming a three dimensional network on the drug crystals.
This might have eventually resulted in efficient adsorption of chitosan
on the drug crystals. Hence, these cocrystals can improve the solubility
of the drug [18,33]. If the e concentration of the polymer further
increased the dissolution decreases (TCC-7 and TCC-8) due to the
formation thick gel layer of the chitosan on the surface of the drug,
these gel structure will increase the distance between the core TEL
crystals from the outside solvent imbibing. These results are well
corroborated by a previous study that described acyclovir cocrystals
prepared by chitosan [38].
3.7. In vivo pharmacokinetics evaluation study
The ultimate goal of TEL cocrystals prepared using a biodegradable
polymer is to improve the drug's oral bioavailability. The evaluation of
the bioavailability of the drug in animals is an important parameter to
consider when preparing new dosage forms. The plasma drug levels
after a 1 mg/kg single dose of pure drug and of TEL cocrystals are
shown in Table 2 and Fig. 7. A significant increase in the peak plasma
concentration (Cmax) was observed for TEL cocrystals (1.47 μg/ml)
over that of pure TEL (0.96 μg/ml). The pharmaceutical practical
implication of these cocrystals is significant, since the ability to form a
supersaturated solution, even transiently that can dramatically affect
the absorption and bioavailability. The level of plasma drug concentra-
tions was increased in the cocrystals. The elimination rate constant (Kel)
of TEL cocrystals (0.0085 h−1) was higher than that of the pure drug
(0.0048 h−1). The improved area under the curve (AUC) (14.62 μg/ml)
Table 2
Pharmacokinetic parameters.
S. No Pharmacokinetics parameters TEL pure drug TEL cocrystals
1. Cmax (ng/ml) 0.96 1.47
2. AUC (ng·ml−1·hr) 10.44 14.62
3. Kel (hr−1) 0.0048 0.0085
4. Relative bioavailability (%) – 140.03
884 M. Ganesh et al. / International Journal of Biological Macromolecules 131 (2019) 879–885
Fig. 7. In-vivo pharmacokinetics of selected formulation.
was found in TEL cocrystals. The increase in Cmax can be attributed to the
increase in the dissolution and absorption rates of the drug. The improved
gastrointestinal absorption may result because the positive charge of the
chitosan is the factor responsible for interaction with the negative site of
the tight junction and the subsequent widening of the paracellular
transport route [39] which is an advantage of chitosan cocrystals over
the conventional acid (or) salt based cocrystals reported in the previous
studies [33,34]. Unlike other salt based cocrystals chitosan like polymers
will support for the mucoadhesion that may also tends raise the contact
between the drug and biological membrane and increasing the bioavail-
ability. Further the chitosan cocrystals are more advantageous when
compared to the chitosan TEL solid dispersion reported earlier inters
uniform formation because the both drug and coformer was added
in solution form into the salting out agent, but in the reported solid
dispersion technique drug only dissolved in the solvent of choice they
selected but not polymer hence improper deposition of drug over the
polymer may possible during the co-evaporation stage [29] that will
leads to variations drug distribution that results alterations in bioavail-
ability of final formulations.
4. Conclusions
In summary, from the results obtained it was strongly evidenced
that the formed chitosan -telmisartan cocrystals have improved solubil-
ity and bio availability with certain ratios of drug and polymer used. In
our case the ratios from 1:1 to 1:6 weight ratio of drug to polymer
ratio support for the continual improvement of solubility of the drug,
while the same on further increasing the polymer will tend to decrease
the solubility hence we chosen the 1:6 as the favourable highest drug
polymer ratio for excellent solubility. From the results of SEM and
PXRD it was clearly observed the crystals structure of telmisartan was
lost with higher polymer concentration. Further the selected formulation
(1:6, TCC-6) increases the in vivo bioavailability of the drug considerably
at high level when compared to pure telmisartan (one-fold increase)
with better AUC and Cmax. A biodegradable polymer like chitosan are
considered to a safe polymer for formulating pharmaceutical formulation
due to their bio stability and toxic free nature when compared to other
cocrystals formulation of telmisartan with citric, gallic, or saccharin like
co-formers. The above listed co-formers have ability to change the pH
of microenvironment from where they get absorbed upon disassociated.
Such consequences will not develop with bio degradable polymers.
Further the process reported herein is very simple and easy to adopt
for scale up. With this we conclude that the chitosan based cocrystals
are one of best choice improve the solubility and bioavailability of not
only the telmisartan but also have the ability to improve the for other
solubility and bioavailability poor soluble drug upon evaluation.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ijbiomac.2019.03.141.
Acknowledgement
This work was financially supported by the Hanseo University Intra-
mural Research Grant 2018.
Declaration of conflicts of interest
None.
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