Journal of Molecular Liquids 282 (2019) 162–168

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Journal of Molecular Liquids

journal homepage: www.elsevier.com/locate/molliq

Synthesis, characterization and studies on host-guest interactions of

inclusion complexes of metformin hydrochloride with β–cyclodextrin
Kuljit Kaur a, Rajeev Jindal a,⁎, Dhruvi Jindal b
a
Department of Chemistry, Dr B R Ambedkar National Institute of Technology, Jalandhar 144011, Punjab, India
b
University Institute of Pharmaceutical Sciences, Punjab University, Chandigarh 160014, India

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

Article history: In this research paper, we describe a study on the inclusion complex formation between Metformin hydrochlo-
Received 27 December 2018 ride (MF) and beta-cyclodextrin (β-CD) in order to improve the sustained release, dissolution and oral bioavail-
Received in revised form 18 February 2019 ability of the drug MF. Metformin hydrochloride is a drug used for treating non-insulin-dependent diabetes
Accepted 26 February 2019
mellitus and for polycystic ovary syndrome. The host-guest solid inclusion complex of MF with β-CD is prepared
Available online 27 February 2019
by Microwave irradiation method along with conventional methods such as physical mixture, kneading method
Keywords:
and co-precipitation method. The phase solubility studies suggested the 1:1 stoichiometry and revealed the sol-
Inclusion complex ubility of MF is enhanced during the inclusion complex formation between MF and β-CD. The value of the appar-
Phase solubility ent stability constant was found to be 61.11 M−1. The rate of dissolution of the drug was found to be highest (95%
Apparent molar volume in 60 min) for the inclusion complex prepared by microwave irradiation method. Inclusion complexes were char-
Microwave method acterized by using FTIR, FESEM, PXRD, DSC and 1HNMR techniques. All the instrumentation techniques revealed
Metformin hydrochloride that microwave and co-precipitation methods form true inclusion complexes. Different parameters such as ap-
parent molar volume (Vϕ), partial molar volume at infinite dilution (Vϕ0) have been determined by using the ex-
perimental density data. Apparent molar and partial molar parameters concerning volumetric predict that the
host-guest interactions prevailed in the ternary system of MF, β-CD and distilled water. Microwave irradiation
completes the process of inclusion complex formation in a very short duration of time and is a more
environment-friendly method. Thus microwave irradiation can be utilized as an advanced, time-saving and
cost-effective method for the generation of MF/β-CD inclusion complexes.
© 2019 Elsevier B.V. All rights reserved.

1. Introduction variable biological half-life (0.9–2.6 h) [2]. The absorption of MF is limited

Metformin hydrochloride (MF) is an oral antidiabetic drug is consid-
ered as the first line pharmacological therapy to treat high blood sugar
levels in the management of type-2 diabetes. Metformin hydrochloride
is used in combination with diet and exercise. Another well-known ben-
efit of Metformin hydrochloride is modest weight loss and also prescribed
to the females suffering from polycystic ovary syndrome. This drug may
be used as part of a combination with other drugs. The chemical name
of Metformin hydrochloride is N, N-dimethylimidodicarbonimidic di-
amide hydrochloride. MF is a white to off-white crystalline compound
with the molecular weight 165.63 and molecular formula C4H11N5. HCl
[1]. This drug is soluble in water and practically insoluble in acetone. It's
relatively low (50–60%) bioavailability together with its short and
Abbreviations: IC, Inclusion complex; β-CD, Beta cyclodextrin; MF, Metformin
hydrochloride; PM, Physical mixture; KN, Kneading; CP, Co-precipitation; MW,
Microwave.
⁎ Corresponding author.
E-mail address: jindalr@nitj.ac.in (R. Jindal).
to the upper gastrointestinal (GI) tract.
This limitation can be removed by preparing the sustained-release
systems of the drug. There are several ways to enhance the solubility
of the drug, to increase bioavailability and sustained release of the
drug such as reduction in particle size of the drug, solid dispersion for-
mulation, pH control of the microenvironment, nanoparticles formula-
tion, lipid-based formulation, superficial fluid process, solubilisation
by agents and complexation with cyclodextrins [3–6]. Among all, com-
plexation with cyclodextrins has proven to be quite an efficient method.
The inclusion complexes of drugs, metal ions or many organic ligands in
cyclodextrins (CDs) represent a group of the simplest supramolecular
structures widely studied for the last several decades. Such inclusion
complexes have improved drug solubility, stability, dissolution and
oral bioavailability [7,8]. These are widely used and made to increase
drug water solubility.
Cyclodextrins (CDs) are macrocyclic oligosaccharides which poly-
mers having 6, 7 and 8 glucose units for α-, β- and γ-CDs, respectively.
Cyclodextrins are produced after enzymatic degradation of starch in
presence of Bacillus macerans. They CDs consists of alpha-1,4-linked
alpha-D-glucopyranose units arranged in “chair conformation” so that

https://doi.org/10.1016/j.molliq.2019.02.127
0167-7322/© 2019 Elsevier B.V. All rights reserved.
 K. Kaur et al. / Journal of Molecular Liquids 282 (2019) 162–168 163

the molecules are shaped like a hollow truncated cone [8–10]. The cy- by using triple distilled water. All the solutions were prepared just before
clodextrins have a torus structure with primary and secondary hydroxyl taking UV and fluorescence measurement.
groups are oriented outwards of the cone making the external molecu-
lar surface hydrophilic hydrophobic internal cavity. A central apolar
2.2. Instruments
cavity with a small number of water molecules located in it is the dis-
tinctive feature of the cyclodextrin molecular structure. This cavity en-
FTIR spectroscopic studies of β-CD: MF inclusion complex were car-
ables the CDs to encapsulate lipophilic molecules like drugs and can
ried out by using Aglient Technologies Carry 630 FTIR Spectrophotome-
change the physicochemical properties of the drug and other wide
ter possessing diamond crystal, in the range of 400 cm−1to 4000 cm−1.
range of solid, liquid and gaseous hydrophobic compounds [11].
A disc of inclusion complex was formed by applying a pressure of
There are many new applications of cyclodextrins in pharmaceutics
6894.76 Pa in a moisture free atmosphere. Powdered XRD pattern of
[8,9,12–15], food [16–18], cosmetics, in environmental protection
β-CD: MF inclusion complex were drawn using panalytical X'Pert Pro
[19], biotechnology, cell biology, biosensing [20] etc. Among all par-
multipurpose diffraction (MPD) with Cu-Kα radiation of wavelength
ent CDs, β-CD has the lowest aqueous solubility (1.85 g/100 mL H2O)
1.54 A° at 298 K. The data was plotted between 5° and 90° in 2θ and
and is the widely chosen cyclodextrin in the pharmacy, because of its
scan rate of 2° min−1. FESEM studies of β-CD: MF inclusion complex
structure, better complex forming ability, availability, suitable cavity
were carried out on Field Emission Gun SEM (Nova Nano FE-SEM 450
dimensions for encapsulation of drug molecules and economical
FEI) in order to study the morphological features of the backbones and
[11,21–24]. Hence in this study (β-CD) Cyclodextrin inclusion com-
synthesized HPN. Samples of inclusion complexes of MF and β-CD
plex of Metformin hydrochloride was prepared to enhance its solu-
were gold-plated to achieve good conductive effects. High energy elec-
bility, dissolution rate, oral bioavailability and sustained release of
tron beams were used. The micrographs were taken at different magni-
Metformin hydrochloride. Variety of methods had been used for
fications. The 1H NMR spectra of β-CD, MF and β-CD: MF inclusion
the synthesis of the inclusion compounds such as physical mixture,
complex were obtained using a Bruker 400NMR spectrometer at
kneading, solid dispersion, spray/freeze drying, supercritical carbon
400 MHz with D2O and CDCl3 as solvents. UV-VIS analysis of inclusion
dioxide, co-evaporation co-grinding and sealed-heating [25–28]. Al-
complexes of MF and the β-CD was carried out on a Systronics Double
though these methods are competent to generate inclusion com-
Beam UV-VIS Spectrophotometer (2201). Experimental density data
plexes, they are certainly associated with certain limitations.
was obtained by using the Anton Paar Density and Speed of sound ana-
In this point of view, the focus has now shifted to more environmen-
lyzer i.e. DSA 5000 M densimeter. An air/water adjustment or density
tally friendly methods. Recently microwave-assisted synthesis has
check was investigated at 293.15 K with triply distilled, degassed
flourished into an interesting area of research. This practice employs a
water, and with dry air at atmospheric pressure. The sensitivity of
minimal amount of solvents, lowers the reaction temperatures and re-
the instrument corresponds to precision in density measurements
duces the amount of by-products [21,29]. This method is easy, environ-
of 1 × 10−3 kg·m−3.
ment friendly, cheap, and can be applied on an industrial scale. True
inclusion complexes of drug atenolol and chlorphenamine with β-CD
are prepared by this method by our group and are well characterized 2.3. Preparation of β-CD: MF inclusion complex
[30,31]. The aim of the present work is to study the complexation of
MF with β-CD, as a possibility of increasing the solubility of this drug 2.3.1. Physical mixture (PM)
in water. The focus of the present work lies to address the effectiveness A physical mixture of MF and the β-CD was prepared by homoge-
and usefulness of the microwave irradiation method for the preparation nous blending of the components in a mortar for 30 min.
of inclusion complexes of MF with β-CD. To compare the efficacy of this
procedure with the conventional methods, inclusion complexes were
also prepared by physical mixing, kneading, and co-precipitation pro- 2.3.2. Kneading method (KN)
cesses. The inclusion complexes of MF and β-CD were characterized A water-ethanol mixture of 20 mL (1:1 v/v) was added to a physical
by FTIR, XRD, DSC, FESEM and 1H NMR spectroscopic techniques. The mixture of MF/β-CD containing 0.0378 g of β-CD and 0.0055 g of MF.
stability constant or solubility constant of the inclusion complex was The resultant mixture was kneaded carefully until the solvent was
calculated from the phase solubility studies and the stoichiometry of completely removed and a homogeneous paste was obtained. The prod-
the inclusion complex of MF and β-CD was found. The dissolution stud- uct collected was dried in a vacuum desiccator overnight to remove the
ies of the inclusion complexes were carried out and compared with the remaining traces of the solvent [21]. Finally, the kneaded inclusion com-
pure MF drug. As per literature survey and to the best of our knowledge plex was ground to fine powder and utilized for further studies.
no work has been published on the inclusion complexes synthesis of MF
and β-CD by microwave method, density and apparent molar volume
2.3.3. Co-precipitation method (CP)
measurements and detailed characterization of these inclusion com-
Briefly, the 0.5 g of β-CD was dissolved in distilled water at 50 °C. The
plexes by using different techniques like FTIR, FESEM, DSC, PXRD and
1
0.08 g of MF was solubilized in ethanol and slowly added to the β-CD so-
HNMR. Thus the novelty of the present work lies in the investigation
lution with continuous stirring. The final solution was refrigerated at 4 °C
of host-guest interactions between MF and β-CD by measuring the den-
for 36 h. The precipitated complex was obtained by filtration and
sity and apparent molar volume. The obtained results intensified the
washed with ethanol to remove the uncomplexed drug. The residue
stability of the inclusion complexes due to the non-covalent interactions
was vacuum-dried for 48 h and utilized for further studies.
among the hosts and guest molecules.

2. Experimental 2.3.4. Microwave method (MW)

2.1. Material and methods
The β-cyclodextrin (β-CD) used to prepared inclusion complexes with
the drug were procured from Sigma Aldrich, India. Metformin hydrochlo-
ride obtained as a gift sample from Ranbaxy Laboratories Limited
(Himachal Pradesh, India). Deionized water was utilized throughout the
experimentation. A stock standard solution of MF and β-CD are prepared
The solid inclusion complex of MF and β-CD was prepared by mi-
crowave method [21]. The 0.5 of β-CD was dissolved in distilled
water at 50 °C and the 0.08 g of the drug was dissolved in ethanol.
MF and β-CD were taken in the molar ratio of 1:1. The reaction mix-
ture was kept in the microwave for 180 s at 100% power. The precip-
itated β-CD: MF complex was recovered by filtration and washed
with ethanol to remove unreacted CPM. The residue was dried in
vacuum and utilized for further studies.
164 K. Kaur et al. / Journal of Molecular Liquids 282 (2019) 162–168

2.4. Phase solubility studies
Phase solubility studies were performed in an aqueous medium at
room temperature according to the method already reported by Higuchi
and Connors. An excess amount of MF drug (20 mg) was put into 5 mL
of aqueous solution of the β-CD having various concentrations
(0–10 mM) in the sealed glass containers. The reaction mixtures were
shaken on a mechanical shaker for 7 days at 37 °C to attain the equilib-
rium. After attaining the equilibrium, the samples were filtered and di-
luted. The concentration of MF was determined spectrophotometrically
with a UV–Vis spectrophotometer from the absorbance at λmax =
273 nm and comparing it with the calibration plot. The apparent stabil-
ity constant or solubility constant Ks was calculated from the phase sol-
ubility diagram according to the following equation [21]:
slope
Ks ¼
So ð1−slopeÞ
where Ks = solubility constant or apparent stability constant, So = sol-
ubility in the absence of β-CD.
2.5. In vitro drug dissolution studies
The drug MF and the inclusion complexes of MF and β-CD were eval-
uated for dissolution studies in 500 mL of phosphate buffer (pH 7) with
continuous stirring at a speed of 100 rpm at 37 °C. 100 mg of MF or its
equivalent amount of the solid inclusion complexes were investigated
for dissolution studies [21]. At definite time intervals, 3 mL of samples
were withdrawn and examined spectrophotometrically with UV visible
spectrophotometer. The withdrawn samples were replaced with the
same volume of fresh medium. The experiments were performed in
triplicate and the mean data was represented.
3. Results and discussions
3.1. Phase solubility studies
The phase solubility plot of MF and β-CD binary system has been
shown in Fig. 1. It has been clearly observed from the plot, the aqueous
solubility of the MF drug increased linearly as a function of the β-CD.
This type of phase solubility diagram of drug and β-CD can be consid-
ered as AL type according to Higuchi and Connors. The slope was calcu-
lated to be 0.196, which is less than 1, thereby suggesting a 1:1
stoichiometry of the MF and β-CD in the inclusion complex. The value
of the apparent stability constant or solubility constant was found to
be 61.11 M−1, which is in close proximity to the reported Ks
58.96 M−1 value for MF with α-CD [1].
3.2. Density and apparent molar volume
The experimental values of solution densities along with the values
of apparent molar volume, of β-CD in (0.010) mol·kg−1 aqueous solu-
tion of MF was measured at different temperatures T = (298, 308, and
318) K. Apparent molar volume for the ternary mixture has been calcu-
lated by using the following equation:
V ϕ ¼ ½ðM=ρÞ−fðρ−ρ0 Þ=ðmA ρρ0 Þg ð2Þ
where mA is the molality of the β-CD, M is the molar mass of the solute
(kg·mol−1), ρ0 and ρ are the densities (kg·m−3) of the solvent and so-
lution. Apparent molar volume (m3·mol−1) and experimental density
ð1Þ for β-CD in (0.010) mol·kg−1 aqueous solutions of MF (at T =
(298.15, 308.15, 318.15) K has been listed in Table 1. By analyzing
Table 1, it is seen that at an individual concentration of MF, the density
of solution rises with an increase in the concentration of β-CD and falls
with an increase in temperature of the solution. It is observed that the
values of apparent molar volume Vϕ are all positive at different temper-
atures as well as concentrations which indicate solute-solvent interac-
tions present in the selected ternary mixtures [32,33]. The partial
molar volume at infinite dilution, Vϕ0 values is 1132.28, 1132.58 and
1134.44 at 298.15, 308.15 and 318.15 K respectively. These results
were found because of the stability of the inclusion complexes inten-
sifies due to the non-covalent forces such as hydrogen bonding, hydro-
phobic interactions, Van der Waals attractions etc. between the hosts
(β-CD) and guest (MF) molecules.
3.3. Analyses of the solid MF/β-CD inclusion complexes
3.3.1. FTIR analysis
The FTIR spectra of the β-CD, MF and PM are represented in Fig. 2a.
The FTIR spectra of KN, CP and MW are depicted in Fig. 2b. The β-CD
had shown key peaks at around 3400 cm−1 to 3200 cm−1 (O\\H
stretching) [34,35] 2932 cm−1 (C\\H stretching) and 1027 cm−1
(C\\O\\C bending). Meanwhile, the frequencies of Metformin hydro-
chloride were recorded at 3370 cm−1 and 3298 cm−1, which corresponds
to the (N\\H) asymmetric and symmetric stretching vibration respec-
tively. The peak at 3170 cm−1 represents (N\\H) symmetric stretch
band lowered due to conjugation. The frequencies at 1628 cm−1 and
1541 cm−1 correspond to bending vibration of (N\\H) [36,37]. The
peaks at 1165 cm−1, 1033 represent (C\\N) stretching frequencies [38].
At 1446 wave numbers, a peak is also observed which revealed the pres-
ence of C\\H (in-plane bending) [31]. The FTIR spectrum of PM was found

Table 1
Densities, ρ and apparent molar volumes, Vϕ of β-CD in (0.010) mol·kg−1 aqueous solu-
tion of Metformin hydrochloride (MF) were measured at different temperatures and at-
mospheric Pressure p = 0.1 MPa.
a
mA/(mol·kg−1) ρ × 10−3 / (kg·m−3) Vϕ × 106 / (m3·mol−1)

T= T= T= T= T= T=
298.15 K 308.15 K 318.15 K 298.15 K 308.15 K 318.15 K

β-CD + 0.010 mol·kg−1 Metformin hydrochloride (MF)

0.000 0.997503 0.996101 0.994183
0.010 0.997559 0.996170 0.994254 1132.19 1132.39 1134.36
0.015 0.997587 0.996203 0.994290 1132.13 1132.35 1134.32
0.020 0.997615 0.996239 0.994325 1132.10 1132.31 1134.28
0.025 0.997643 0.996276 0.994361 1132.07 1132.19 1134.24
0.030 0.997671 0.996311 0.994396 1132.03 1132.13 1134.19
0.035 0.997699 0.996346 0.994432 1132.00 1132.09 1134.15
0.040 0.997729 0.996383 0.994467 1131.92 1132.00 1134.11
0.045 0.997758 0.996419 0.994503 1131.87 1131.94 1134.07
0.050 0.997786 0.996454 0.994538 1131.84 1131.91 1134.03
a
Fig. 1. The phase solubility diagram for the inclusion complex of MF and β-CD. mA is the molality of β-CD in aqueous MF solution.
 K. Kaur et al. / Journal of Molecular Liquids 282 (2019) 162–168 165

250
a) b)
200 MW
PM

2930
3372
3292
200

3157
3370
3297

3069

1152.7

939.9
3152

1158
1628
1553

%Transmittance
% Transmittance

1027.1
1033
150
CP
150 MF

2934
3372
3297
3158

933.3
3298
3370

3152
3074

1628

1165
1446
100

1033
1541

1058
100 KM

3370
3293
-CD

3157
2871

933.3
2932
3270

1628

1027
1058
1528 50
50 4000 3500 3000 2000 1500 1000 500
4000 3500 3000 2000 1500 1000 500 -1
Wave number (cm )
-1
Wavenumber (cm )

0 20 40 60 80 100 0 20 40 60 80 100
40
38.7

44.5

c)
28.8

30
35.07

d)

78.4
27.2

30.7

56.4

67.7
30

38.5

49.2
44.5

60.0
MW
31.9

52.9

60.4

PM
21.3

20
20

10 10

30.7 31.9

45.7
Intensity (counts)
Intensity (counts)

65.5
49.1
17.2
60
22.04

44.2

58.4
30

36.2
27.8
30.8
35.2

74.6
CP
17.2

25.7
22.8
29.2

38.5
11.8
12.3

MF

22.2
40
44.5

20
60.4

20
10
0
8000
30 KN
12.7

6000
CD

44.5
22.8

59.7
21.3
10.7

27.2

4000 20
34.7

2000
10
0
0 20 40 60 80 100 0 20 40 60 80 100
2 (degree) 2 (degree)

Fig. 2. FTIR spectra of a) β-CD, MF and PM b) KN, CP and MW. PXRD pattern of c) β-CD, MF and PM d) KN, CP and MW.

to be a superposition of the parent components, which indicate that there The diffraction profile of KN (Fig. 2d) exhibits some new peaks along
is no evident interaction. In the spectrum of KN, the key MF and β-CD with the peaks due to drug MF and β-CD which point towards incom-
peaks were both present but with small shifts from their original positions plete complexation. The diffractogram of CP and MW (Fig. 2d) demon-
suggesting an incomplete interaction. For CP and MW, shifts in the char- strate completely different characteristics relative to the parent
acteristic peaks of parent components were observed (Fig. 2b). The components. CP exhibited new peaks at 38.5°, 45.7°, and 49.1° which
C\\N peak of MF had shifted to a lower frequency in CP and MW (from advised the crystalline nature. In the XRD profile of MW, sharp peaks
1165 cm−1 and 1033 cm−1 to 1152.7 cm−1 and 1027.1 cm−1). New are observed at 7.5°, 9.5°, 13.8° etc., and the diffraction profile is
peaks were observed in the region of 2934 and 2930 cm−1 in CP and completely dissimilar from the parent compounds. The Sharp peaks at
MW. The shift in C\\N stretching vibration in case of CP and MW to 38.5°, 56.4°, 67.7°, and 78.4° in the XRD pattern of the MW confirm
lower frequency region is attributed to hydrogen bonding interaction be- the diffraction profile which is completely different from the parent
tween the N\\H of MF and hydroxyl group of the β-CD. This clearly indi- compounds. Thus, the synthesis of the true inclusion complex by the mi-
cates that the N\\H group is involved in the interaction of MF with β-CD crowave irradiation method is evident from its XRD data.
in these inclusion complexes. Thus the FTIR Spectra significantly proves
the formation of Metformin hydrochloride and β-CD inclusion complex. 3.3.3. SEM analysis
The surface morphology of the β-CD, MF and different kind of inclu-
3.3.2. Powdered X-ray diffraction studies sion complexes of drug MF and β-CD is studied by scanning electron mi-
Powdered X-ray diffraction has been used as one of the important croscopy. The SEM images of the β-CD, MF, PM, KN, CP, MW is given in
tools to observe MF–β-CD inclusion complex formation. The diffraction Fig. 3(a–f). The micrographs of the β-CD (Fig. 3a) and MF (Fig. 3b) were
profile of the inclusion complex is generally different from those of the found to be crystalline with different dimensions and polyhedral in na-
individual components. The XRD pattern of β-CD (Fig. 2c) represents ture. The SEM image of PM and KN (Fig. 3c, d) exhibited both the parti-
the sharp peaks at 10.7°, 12.7°, 22.8°, and 27.4° which suggest β-CD is cles of the β-CD and MF. In the rest of the inclusion complexes, CP and
crystalline in nature. Sharp peaks at 17.2°, 22.04°, 22.8°, 27.8°, 29.2°, MW (Fig. 3e, f) the morphology was found to be totally different from
30.8° and 35.2° in the XRD profile of MF also indicate the highly crystal- those of the parent compounds with larger dimension [30,39,40]. Thus
line nature of MF. The diffraction profile of the PM shows the features of the SEM images proved qualitatively the formation of new entities of in-
both β-CD and MF which suggest that no new crystal has been formed. clusion complex from the drug MF and β-CD.
166 K. Kaur et al. / Journal of Molecular Liquids 282 (2019) 162–168

a b

c d

e f

Fig. 3. FESEM images of a) β-CD b) MF c) PM d) KN e) CP f) MW.

3.3.4. Differential scanning calorimetry
DSC has been found as an important criterion for the identification
and characterization of inclusion complexes of the β-CD and drug.
When MF drug molecules are entrapped in the β-CD cavities; their
melting, boiling, or sublimating points generally shift to different tem-
peratures or disappear completely. The DSC thermograms of the β-CD,
MF, PM, KN, CP and MW are shown in figure. The DSC curve (Fig. 4a)
of the β-CD showed a broad endothermic effect around 75.5 °C which
is associated with its dehydration process. The thermogram of MF was
typical of a crystalline anhydrous substance with a sharp endotherm
around 227 °C indicating its melting point. The thermograms of PM
and KN samples revealed the downward shift in the endothermic
peak of MF. This might be due to the weak hydrogen bonding interac-
tions between NH and NH2 groups of MF and \\OH groups of the β-
CD and incomplete insertion of the MF into the cavity of β-CD. The ther-
mograms of CP and MW revealed a more downward shift in the endo-
thermic peaks of MF than PM and KN. This might be due to the strong
physical interactions among the functional groups of MF and β-CD.
The drug MF gets embedded efficiently into the cavity of β-CD and con-
firms the formation of true inclusion complexes.
 K. Kaur et al. / Journal of Molecular Liquids 282 (2019) 162–168 167

Table 2b
(a)
Chemical shift δ and Δδ of protons of MF in free MF, PM, KM, CP and MW.
-CD
o
75.88 N(CH3)2 protons Δẟ
Heat flow, Endo down

o MW MF 2.9780
181.9
PM 2.9862 0.0082
KN 2.990 0.0120
o
CP CP 2.9888 0.0108
181.1
MW 2.9872 0.0092
KN Comment Downfield
o
191.1

PM
196.1
o shifts of the drug protons also get influenced by the presence of β-CD.
Thus the downfield shift of\\N (CH3)2 protons in PM, KN, CP and MW
MF
o were observed in the 1HNMR spectrum (Table 2b). This deshielding of
227
drug protons confirmed the drug gets embedded efficiently in the cavity
0 200 400 600 800 of β-CD and inclusion complex formation has taken place.
o
Temperature ( C)
3.4. In vitro drug dissolution studies

The dissolution curves of MF and MF/β-CD inclusion complexes in

phosphate buffer (pH 7) are displayed in Fig. 4b. As evident from
100 (b) Fig. 4b, the dissolution of pure MF is very low even after 60 min. This
MW could be due to the poor aqueous solubility of the drug. The dissolution
80 of MF was enhanced on physically mixing β-CD with the drug. The KN
CP showed a further increase in dissolution rate as compared to that of
PM. However, the dissolution rates were much higher for the CP and
% MF released

60 MW as compared to PM and KN inclusion complexes. The better results

KN for MW were investigated due to enhanced solubility of the drug, more
40 amorphization of the drug, improved wettability and reduced particle
size due to intermolecular hydrogen bonding. At any given time the dis-
PM solution rate was found to be higher for MW inclusion complexes,
20 which proved the effectiveness and efficiency of this method over
MF others.
0
4. Conclusions
0 10 20 30 40 50 60
The microwave irradiation method used to prepare solid inclusion
Time (min)
complexes of MF with β-CD and compared with the conventional
methods of physical mixing, kneading and co-precipitation. The phase
Fig. 4. a) DSC thermograms of β-CD, MF, PM, KN, CP and MW. b) In vitro dissolution profile
of MF (pure drug), PM, KN, CP and MW inclusion complexes. solubility studies of MF/β-CD suggested the 1:1 stoichiometry and re-
vealed the solubility of MF is enhanced during the inclusion complex
formation between MF and β-CD. The instrumental characterization re-
3.3.5. 1HNMR sults indicated the formation of true inclusion complexes by the CP and
The formation of drug-β-CD inclusion complex can be proved by 1H MW methods. Microwave irradiation method uses minimal amounts of
NMR studies (Fig. 1S in supporting information). The hollow cone topol- solvents and the complex formation is accomplished within a short du-
ogy of the β-CD with protons H-3 and H-5 being the inner protons is ration of time. The rate of dissolution of the drug in MW was found to be
well studied. The hydrophobic guests like drugs get embedded in the 95% in 60 min, which is the highest among other methods of inclusion
cavity of β-CD thereby changing the chemical shifts of inner protons. complex formation. The apparent stability constant was found to be
In 1HNMR of β-CD, PM, KN, CP and MW, the H-3 and H-5 signals of 61.11 M−1. Better efficacy of the inclusion complexes prepared with
the β-CD showed significant changes in chemical shifts (Table 2a). The MW method was observed in terms of dissolution properties, density
inclusion complex synthesized by microwave method (MW) revealed and apparent molar volume measurements of MF and β-CD. The posi-
the significant upfield shifts in the chemical shifts of H-3 and H-5 pro- tive values of partial molar volume at infinite dilution, Vϕ0 suggests the
tons of the β-CD. It is noteworthy that the H-3 and H-5 protons shifted solute-solvent interactions exist in the form of non-covalent forces
about 0.040 and 0.020 ppm respectively in MW. Thus the chemical shift such as hydrogen bonding, hydrophobic interactions, Van der Waals at-
variations in the positions of H-3 and H-5 of the β-CD in the inclusion tractions exist. Thus microwave irradiation method of inclusion com-
complex reflect the formation of an inclusion complex. The chemical plex preparation can be exploited as an improved, cheap and time-
saving method and can be utilized to prepare true complexes of MF
with β-CD.
Table 2a Supplementary data to this article can be found online at https://doi.
δ and Δ(δ) of protons in β-CD, PM, KN, CP and MW inclusion products. org/10.1016/j.molliq.2019.02.127.
Proton ẟ β-CD ẟ PM ẟ KN ẟ CP ẟ MW Δẟ PM Δẟ KN Δẟ CP Δẟ MW
Acknowledgements
H-1 4.990 5.010 5.010 5.010 5.000 0.020 0.020 0.020 0.010
H-2 3.580 3.601 3.601 3.600 3.595 0.021 0.021 0.02 0.015
H-3 3.890 3.890 3.892 3.892 3.850 0.000 0.002 0.002 0.040 One of the authors Kuljit Kaur is highly grateful to MHRD for provid-
H-4 3.510 3.540 3.530 3.530 3.519 0.030 0.020 0.020 0.009 ing financial assistance to carry out research. The author is also thankful
H-5 3.780 3.782 3.784 3.780 3.760 0.002 0.004 0.000 0.020 to SAIF facility, Punjab University Chandigarh, Instrumentation centre,
H-6 3.790 3.810 3.809 3.811 3.790 0.020 0.009 0.021 0.000
IIT Roorkee, for different characterization of samples and DST-FIST for
168 K. Kaur et al. / Journal of Molecular Liquids 282 (2019) 162–168

providing financial assistance for procurement of type of equipments [21] S. Das, U. Subuddhi, Studies on the complexation of diclofenac sodium with β-
cyclodextrin: influence of method of preparation, J. Mol. Struct. 1099 (2015)
like FTIR and UV–Visible spectrophotometer used in the characteriza- 482–489, https://doi.org/10.1016/j.molstruc.2015.07.001.
tion of the samples. [22] L. Jin, Q. Liu, Z. Sun, X. Ni, M. Wei, Preparation of 5-fluorouracil/β-cyclodextrin complex
intercalated in layered double hydroxide and the controlled drug release properties,
Ind. Eng. Chem. Res. 49 (2010) 11176–11181, https://doi.org/10.1021/ie100990z.
References [23] L.D. Wilson, R.E. Verrall, Volumetric study of modified beta-cyclodextrin/
hydrocarbon and /fluorocarbon surfactant inclusion complexes in aqueous solu-
[1] S.L. Roselet, J. Premakumari, Studies on Metformin Hydrochloride and α-
tions, J. Phys. Chem. B 102 (1998) 480–488, https://doi.org/10.1093/petrology/42.
Cyclodextrin Inclusion Complexes, Green Chemistry & Technology Letters. 1
3.555.
(2015) 48–53. doi:10.18510/gctl.2015.117.
[24] J. Azzi, P. Danjou, D. Landy, S. Ruellan, L. Auezova, H. Greige-gerges, S. Fourmentin,
[2] G. Corti, M. Cirri, F. Maestrelli, N. Mennini, P. Mura, Sustained-release matrix tablets
The effect of cyclodextrin complexation on the solubility and photostability of
of metformin hydrochloride in combination with triacetyl-b-cyclodextrin, Eur. J.
nerolidol as pure compound and as main constituent of cabreuva essential oil,
Pharm. Biopharm. 68 (2008) 303–309, https://doi.org/10.1016/j.ejpb.2007.06.004.
Beilstein J. Org. Chem. (2017) 835–844, https://doi.org/10.3762/bjoc.13.84.
[3] R. Ficarra, P. Ficarra, M.R. Di Bella, D. Raneri, S. Tommasini, M.L. Calabro, A. Villari, S.
[25] R.H. Walters, B. Bhatnagar, S. Tchessalov, K. Izutsu, Next-generation drying technol-
Coppolino, Study of the inclusion complex of atenolol with β-cyclodextrin, J. Pharm.
ogies for pharmaceutical, J. Pharm. Sci. (2014) 1–23, https://doi.org/10.1002/jps.
Biomed. Anal. 23 (2000) 231–236.
23998.
[4] S. Prabu, K. Sivakumar, S.K. Nayaki, R. Rajamohan, Host-guest interaction of cytidine
[26] R. Chadha, S. Gupta, G. Shukla, D.V.S. Jain, S. Singh, Characterization and in vivo effi-
in β-cyclodextrin microcavity: characterization and docking study, J. Mol. Liq. 219
cacy of inclusion complexes of sulphadoxine with b-cyclodextrin: calorimetric and
(2016) 967–974, https://doi.org/10.1016/j.molliq.2016.04.017.
spectroscopic studies, J. Incl. Phenom. Macrocycl. Chem. (2011) 149–159, https://
[5] D. Kanjickal, S. Lopina, M.M. Evancho-Chapman, S. Schmidt, D. Donovan, Improving
doi.org/10.1007/s10847-010-9919-9.
delivery of hydrophobic drugs from hydrogels through cyclodextrins, J. Biomed.
[27] A. Antony Muthu Prabhu, V.K. Subramanian, N. Rajendiran, Excimer formation in in-
Mater. Res. Part A. 74A (2005) 454–460, https://doi.org/10.1002/jbm.a.30374.
clusion complexes of β-cyclodextrin with salbutamol, sotalol and atenolol: spectral
[6] S.K.S. Kushwaha, A.K. Rai, S. Singh, Formulation of thermosensitive hydrogel con-
and molecular modeling studies, Spectrochim. Acta - Part A Mol. Biomol. Spectrosc.
taining cyclodextrin for controlled drug delivery of camptothecin, Trop. J. Pharm.
96 (2012) 95–107, https://doi.org/10.1016/j.saa.2012.04.044.
Res. 13 (2014) 1007–1012, https://doi.org/10.4314/tjpr.v13i7.1.
[28] R. Zhao, C. Sandström, H. Zhang, T. Tan, NMR study on the inclusion complexes of β-
[7] R. Singh, N. Bharti, J. Madan, S.N. Hiremath, Characterization of cyclodextrin inclu-
cyclodextrin with isoflavones, Molecules. 21 (2016) 1–11, https://doi.org/10.3390/
sion complexes - a review introduction, Journal of Pharmaceutical Science and Tech-
molecules21040372.
nology. 2 (2010) 171–183.
[29] S. Das, U. Subuddhi, Exploring poly(vinyl alcohol) hydrogels containing drug-
[8] L.Ţ.A.M. Miclea, L. Vlaia, V. Vlaia, D.I.H.Ă.D.Ă.R.U.G. Ă, C. Mircioiu, Preparation and
cyclodextrin complexes as controlled drug delivery systems, J. Appl. Polym. Sci.
characterisation of inclusion complexes of meloxicam and α-cyclodextrin and β-
131 (2014) 1–13, https://doi.org/10.1002/app.40318.
cyclodextrin, farmacia. 58 (2010) 583–593.
[30] K. Kaur, R. Jindal, Exploring RSM-CCD-optimized chitosan-/gelatin-based hybrid
[9] M. Prabaharan, J.F. Mano, Chitosan derivatives bearing cyclodextrin cavitiesas novel
polymer network containing CPM–β-CD inclusion complexes as controlled drug de-
adsorbent matrices, Carbohydr. Polym. 63 (2006) 153–166, https://doi.org/10.1016/
livery systems, Polym. Bull. (2018)https://doi.org/10.1007/s00289-018-2555-z.
j.carbpol.2005.08.051.
[31] K. Kaur, R. Jindal, D. Jindal, RSM-CCD optimized microwave-assisted synthesis of chi-
[10] Z. Deng, Y. Guo, X. Zhao, P.X. Ma, B. Guo, Multifunctional stimuli-responsive
tosan and gelatin-based pH sensitive, inclusion complexes incorporated hydrogels
hydrogels with self-healing, high conductivity, and rapid recovery through host-
and their use as controlled drug delivery systems, J. Drug Deliv. Sci. Technol.
guest interactions, Chem. Mater. 30 (2018) 1729–1742, https://doi.org/10.1021/
(2018)https://doi.org/10.1016/j.jddst.2018.09.003.
acs.chemmater.8b00008.
[32] H. Kumar, I. Behal, Densities and speeds of sound of antibiotic drug chloramphenicol
[11] J.S. Patil, D. V Kadam, S.C. Marapur, M. V Kamalapur, Inclusion Complex System; a
with L-leucine and glycyl-L-leucine in aqueous medium at T = (288.15 − 318.15) K:
Novel Technique To Improve the Solubility and Bioavailability of Poorly Soluble
a volumetric, ultrasonic, and UV absorption study, J. Chem. Eng. Data (2016)https://
Drugs: a Review, Int. J. Res. Pharm. Sci. Rev. Res. 2 (2010) 29–34. doi:https://doi.
doi.org/10.1021/acs.jced.6b00168.
org/10.1136/bmj.333.7574.873-a.
[33] H. Kumar, V. Kumar, M. Sharma, I. Behal, Studies on the interactions behaviour of
[12] M. Bogdan, M.R. Caira, D. Bogdan, C. Morari, Evidence of a bimodal binding between
polyhydroxy solutes D(+)-glucose and D(−)-fructose in aqueous triammonium cit-
diclofenac-Na and β-cyclodextrin in solution, J. Incl. Phenom. Macrocycl. Chem.
rate solutions over temperature range T = (288.15–318.15) K, J. Chem. Thermodyn.
(2018) 225–229https://link.springer.com/article/10.1023%2FB%3AJIPH.0000048311.
119 (2018) 1–12, https://doi.org/10.1016/j.jct.2017.12.003.
02653.23%0Ahttp://files/1400/10.1023BJIPH.0000048311.02653.html.
[34] M. Naushad, T. Ahamad, B.M. Al-Maswari, A. Abdullah Alqadami, S.M. Alshehri,
[13] Y. Horiuchi, K. Abe, F. Hirayama, K. Uekama, Release control of theophylline by
Nickel ferrite bearing nitrogen-doped mesoporous carbon as efficient adsorbent
jkyclodextrin derivatives: hybridizing effect of hydrophilic, hydrophobic and ioniz-
for the removal of highly toxic metal ion from aqueous medium, Chem. Eng. J.
able p-cyclodextrin complexes, J. Control. Release 15 (1990) 1–7.
330 (2017) 1351–1360, https://doi.org/10.1016/j.cej.2017.08.079.
[14] D.C. Bibby, N.M. Davies, I.G. Tucker, Mechanisms by which cyclodextrins modify
[35] A. Kumar, G. Sharma, M. Naushad, S. Thakur, SPION/b-cyclodextrin core – shell
drug release from polymeric drug delivery systems, Int. J. Pharm. 197 (2000)
nanostructures for oil spill remediation and organic pollutant removal from waste
1–11, https://doi.org/10.1016/S0378-5173(00)00335-5.
water, Chem. Eng. J. 280 (2015) 175–187, https://doi.org/10.1016/j.cej.2015.05.126.
[15] T. Yamanobe, H. Takeda, Y. Takada, D. Nagai, M. Yoneyama, H. Uehara, Structure and
[36] K. Kaur, R. Jindal, Synergistic effect of organic-inorganic hybrid nanocomposite ion
physical properties of poly (lactic acid) and cyclodextrin composite, J. Incl. Phenom.
exchanger on photocatalytic degradation of rhodamine-B dye and heavy metal ion
Macrocycl. Chem. 0 (2018), 0. https://doi.org/10.1007/s10847-018-0859-0.
removal from industrial effluents, J. Environ. Chem. Eng. 6 (2018) 7091–7101,
[16] T. Aree, S. Jongrungruangchok, β-Cyclodextrin encapsulation elevates antioxidant
https://doi.org/10.1016/j.jece.2018.09.065.
capacity of tea: a closing chapter on non-epicatechins, atomistic insights from X-
[37] K. Kaur, R. Jindal, Comparative study on the behaviour of chitosan-gelatin based hy-
ray analysis, DFT calculation and DPPH assay, Carbohydr. Polym. 194 (2018)
drogel and nanocomposite ion exchanger synthesized under microwave conditions
24–33, https://doi.org/10.1016/j.carbpol.2018.04.016.
towards photocatalytic removal of cationic dyes, Carbohydr. Polym. 207 (2019)
[17] L.J. Yang, B. Yang, W. Chen, R. Huang, S.J. Yan, J. Lin, Host-guest system of nimbin and
398–410, https://doi.org/10.1016/j.carbpol.2018.12.002.
β-cyclodextrin or its derivatives: preparation, characterization, inclusion mode, and
[38] A. Kumar, G. Sharma, M. Naushad, A.H. Al-muhtaseb, A. Kumar, Visible
solubilization, J. Agric. Food Chem. 58 (2010) 8545–8552, https://doi.org/10.1021/
photodegradation of ibuprofen and 2,4-D in simulated waste water using sustain-
jf101079e.
able metal free-hybrids based on carbon nitride and biochar, J. Environ. Manag.
[18] J. Szejtli, L. Szente, Elimination of bitter, disgusting tastes of drugs and foods by cy-
231 (2019) 1164–1175, https://doi.org/10.1016/j.jenvman.2018.11.015.
clodextrins, Eur. J. Pharm. Biopharm. 61 (2005) 115–125, https://doi.org/10.1016/j.
[39] K. Kaur, R. Jindal, R. Tanwar, Chitosan – gelatin @ tin (IV) tungstatophosphate nano-
ejpb.2005.05.006.
composite ion exchanger: synthesis, characterization and applications in environ-
[19] A. Kumar, A. Kumar, G. Sharma, M. Naushad, R.C. Veses, A.A. Ghfar, F.J. Stadler, M.R.
mental remediation, J. Polym. Environ. 0 (2018) 0, https://doi.org/10.1007/
Khan, Solar-driven photodegradation of 17-β-estradiol and ciprofloxacin from
s10924-018-1321-5.
waste water and CO2 conversion using sustainable coal-char/polymeric-g-C3N4/
[40] A. Kumar, A. Kumar, G. Sharma, A.H. Al-muhtaseb, M. Naushad, A.A. Ghfar, F.J.
RGO metal-free nano-hybrids, New J. Chem. 41 (2017) 10208–10224.
Stadler, Quaternary magnetic BiOCl/g-C3N4/Cu2O/Fe3O4 nano-junction for visible
[20] A. Kapor, V. Nikolić, L. Nikolić, M. Stanković, M. Cakić, L. Stanojević, D. Ilić, Inclusion
light and solar powered degradation of sulfamethoxazole from aqueous environ-
complexes of amlodipine besylate and cyclodextrins, Cent. Eur. J. Chem. 8 (2010)
ment, Chem. Eng. J. 334 (2018) 462–478, https://doi.org/10.1016/j.cej.2017.10.049.
834–841, https://doi.org/10.2478/s11532-010-0061-8.