Journal of Molecular Structure 1284 (2023) 135410

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Journal of Molecular Structure

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Molecular dynamics of diclofenac potassium at 300.15 K temperature:

Insights from broadband dielectric, thermal and MD simulation
analysis
J.B. Karakthala a, H.P. Vankar b, V.A. Rana a,∗
a
Department of Physics, School of Sciences, Gujarat University, 380009 Ahmedabad, Gujarat, India
b
Department of Physics, Government Science College, 394430 Vankal, Gujarat, India

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

Article history: Diclofenac potassium (DK) has been categorised as a class II drug by the biopharmaceutics classification
Received 16 September 2022 system (BCS) based on its high permeability and low solubility. Solubility and stability of such a pharma-
Revised 10 March 2023
ceutical medicine must be increased to make a good clinical candidate, which can be accomplished by
Accepted 21 March 2023
understanding its molecular dynamics. In the current study, experimental and computational techniques
Available online 29 March 2023
are used to investigate the structural characteristics and the molecular interactions of DK at 300.15 K
Keywords: temperature. The thermal analysis of DK has been done by differential scanning calorimetry (DSC) and
Diclofenac potassium thermogravimetric analysis (TGA). Molecular dynamics of DK is investigated through broadband dielectric
Pharmaceutical drug spectroscopy (BDS) and molecular dynamic (MD) simulation. Complex permittivity spectra of DK were
Dielectric spectroscopy obtained over two frequency ranges: i) low frequency (20 Hz ≤ f ≤ 2 MHz) and ii) high frequency (0.2
MD simulation ≤ f ≤ 20 GHz). Relaxation mechanism in DK takes place in two ways; one is associated with the re-
Hydrogen bon
orientation of whole molecule, so-called primary (α ) relaxation and other is originated from the small
angle reorientation or group rotation of DK, so-called secondary (β , δ, γ ) relaxation. Interactions be-
tween molecules/atoms/ions form different types of bonds in the DK molecules. Among them, interaction
through H-bond is discussed in detail. Orientational dynamics revealed through DRS data is further con-
firmed by the MD simulation study.
© 2023 Elsevier B.V. All rights reserved.

1. Introduction can be helpful in the development of various DK-containing phar-

Identification of molecular interactions can help to explain var-
ious drug performances including solubility, stability, dissolution,
bioavailability etc. [1–3]. A comprehensive understanding of molec-
ular dynamics of pharmaceuticals unfolds a new research topic for
physicists, chemists, and material scientists working in the sub-
ject of pharmaceutical research. The diclofenac potassium (DK) is
chemically designated as 2-[(2,6 dichlorophenyl) amino] benzene
acetic acid mono potassium salt; and is commonly prescribed for
pain management in several inflammatory diseases [4,5]. DK has a
strong reactivity and excellent tolerability due to its unique struc-
tural characteristics. Their mutual interplay defines the drug struc-
tural stability and inhibition activity [6]. Intramolecular H-bond,
which was validated during the X-ray investigation [7] is one of
the fundamental characteristics defining the diclofenac structure.
The study of DK’s structural and inter/intra molecular interactions
∗
Corresponding author.
E-mail addresses: jignakarakthala@gujaratuniversity.ac.in (J.B.
varana@gujaratuniversity.ac.in (V.A. Rana).
macological products that are tailored to specific needs, such as
enhancing the efficacy, tolerability, and comfort of the medica-
tion for the patient [6,8]. Additionally, the literature suggests that
the intramolecular H-bond in DK is used to modify the medica-
tion with, for example, transition metals [9], cyclodextrin [10], or
PEG [11], to boost its water solubility and oral bioavailability [6].
Since H-bond is crucial for either the DK modification or the cy-
clooxygenase inhibition, it is necessary to gain insight into specific
inter/intra molecular H-bond interaction, which has been accom-
plished in the current work using thermal, spectroscopic and com-
putational investigations. To the best of our knowledge, the above
investigations are studied for the first time for the DK in its pure
form.
In of view of drug applications, thermal analysis are capable of
revealing important properties like phase transitions [12], stabil-
ity [13,14], shelf life predictions [15], moisture content determina-
tion [13,16], purity determination [17] etc. Thermal analysis tools,
DSC and TGA, are used here to understand chemical processes tak-
ing place in material with temperature and time. It is also used to
Karakthala),
explore the thermal effects present in DK and to examine its pu-

https://doi.org/10.1016/j.molstruc.2023.135410
0022-2860/© 2023 Elsevier B.V. All rights reserved.
J.B. Karakthala, H.P. Vankar and V.A. Rana
rity. The efficacy and safety of a drug can be affected by degrada-
tion products. TGA analysis has been utilized to identify the degra-
dation of products that may form during heating. The broadband
dielectric spectroscopy (BDS) has received increasing attention to
understand the molecular dynamics of pharmaceutical compounds
[18–20]. This technique involves the application of electric field to
a sample and the measurement of the response in the frequency
and/or temperature domains. Analysis in the frequency domain al-
lows to characterize the relaxation behaviour of sample without
necessity of that material undergoing thermal events and affords
the possibility of modelling the response in terms of non-linear
least square fitting using equivalent circuit. BDS is used to in-
vestigate multiple relaxations in material, in which a sample is
placed within an electric field oscillating at frequency ranges from
10−6 Hz to1012 Hz. When electric field is applied, energy is stored
by the polarization (deformation or reorientation) or lost due to
dielectric loss and conductivity loss. Phase lag between excitation
and deexcitation of charges gains a constant value, is related to re-
laxation time for respective dielectric process. Such electric field
induces multiple relaxations as a result of electrode polarization,
ionic polarization, and dipolar polarization [21–25]. The dielec-
tric relaxation behaviour of pharmaceutical drug in frequency do-
main at ambient temperature is important to aid predictability of
storage and many pharmaceutical applications. Thus, the dielectric
study of DK at room temperature (300.15 K) is carried out to re-
veal their relaxation mechanisms in broad frequency range. Here,
both dielectric and electrical processes are assessed using complex
permittivity spectra of DK over two frequency ranges: i) low fre-
quency (20 Hz ≤ f ≤ 2 MHz) and ii) high frequency (0.2 ≤ f ≤
20 GHz). The KWW and HN dielectric models were utilised to un-
derstand the relaxation process of DK, since they were significantly
important for pharmaceutical compounds [18,26–28]. Kohlrausch-
Williams-Watts (KWW) function account for stretched exponen-
tial transient behaviour for individual relaxation mechanism. The
Havriliak-Negami (HN) function accounts the symmetric and asym-
metric broadening of dielectric relaxation process and thus was
utilized along with constant phase element (CPE) term for better
description of complex permittivity spectra.
Nowadays, computational methods are widely used in pharma-
ceutical science to allow researcher to speeding up the drug dis-
covery and decreasing research-associated costs. In the last few
years, there has been a huge rise in the use of MD simulation for
pharmacological applications [29]. MD simulation is useful to pre-
dict the physical stability, solubility, dissolution mechanism, bind-
ing kinetics, interaction mode of drug molecules [29–33]. In this
work, we have studied interaction mode in the form of hydro-
gen bond (H-bond), aromatic H-bond, halogen bond and salt bridge
through MD simulation. We have focused on the application of MD
on three specific types, i.e., radial distribution function, coordina-
tion number and hydrogen bonding.
This investigation provides the structural characteristics of DK
by revealing their movements and configurations of the atoms,
molecules, and ions in the system.
2. Materials and methods
2.1. Sample preparation
DK (C14 H10 Cl2 KNO2 ) (Molecular weight = 334.2 g/mol) was re-
ceived as a gift for academic purpose from Shree Parikh Trading,
Ahmedabad, India with 99.00% purity. DK is a benzene acetic acid
derivate and nonsteroidal anti-inflammatory drug (NSAID) with
analgesic, antipyretic and anti-inflammatory activity. DK consist of
secondary amino group (-NH) bridging two aromatic rings; one is
chlorinated ring (two chlorine) and other is connected by acetate
anion (−CH3 COO− ), and potassium ion (K+ ). DK pellet of thickness
2
Journal of Molecular Structure 1284 (2023) 135410
0.336 cm prepared using the press well hydraulic pelletizer unit
with a pressure 9.807 MPa was used for dielectric measurements.
2.2. DSC and TGA measurements
Mettler Toledo TGA/DSC 1 system along with STARe evaluation
software was used for the DSC measurements and analysis, respec-
tively. The sample weight of 10.08 mg in powder form was sealed
into a pin holed Alumina 7 μl pan and was single scanned with
a constant heating rate of 20 °C/min. The DSC thermographs of
DK was taken in the temperature range of 25 °C to 600 °C un-
der dried nitrogen atmosphere. The DSC cell was calibrated us-
ing indium as standard. Empty aluminium pans were used as ref-
erences. Changes in heat flux over different temperatures of DK
powder were obtained from these measurements. Temperature ac-
curacy was ± 0.2 K. The TGA analysis was performed with Met-
tler Toledo TG-DTA system along with STARe evaluation software.
The sample weighing 10.4265 mg was kept in standard aluminium
40 μl pan as a crucible with a scanning rate of 20 °C/min. The ther-
mographs were taken in the temperature range of 25 °C to 800 °C
under dried nitrogen atmosphere. Change in mass over the differ-
ent temperatures of DK powder were obtained from these mea-
surements. Temperature accuracy was ±1 K.
2.3. DRS measurements and fitting models
Complex permittivity measurements of DK pellet were carried
out at 300.15 K temperature in two frequency ranges: low fre-
quency range (20 Hz ≤ f ≤ 2 MHz) and high frequency range (0.2
≤ f ≤ 20 GHz). Precision LCR metre, E4980A along with dielec-
tric test fixture (Agilent 16451B), was used for measurements of
low frequency parallel capacitance (Cp ) and parallel resistance (Rp ),
which were further utilized to determine the dielectric constant
(ε  ) and dielectric loss (ε  ) using equation reported in reference
[34]. For these measurements, the sample of thickness 0.336 cm
was sandwiched between the top guarded (diameter of 5 mm) and
bottom unguarded (diameter of 56 mm) electrodes of dielectric
test fixture. To eliminate the effect of stray capacitance, short cir-
cuit compensation and correction coefficient of the dielectric test
fixture were considered during the evaluation of low frequency di-
electric data [35]. Accuracy of the determined low frequency com-
plex dielectric permittivity is 0.3%. Anritsu Shockline Vector Net-
work analyzer (VNA) model no. MS46322A along with SPEAG DAK-
TL-P2 base system was utilized for measurement of dielectric con-
stant (ε  ) and dielectric loss (ε  ) in the frequency range 0.2 ≤ f ≤
20 GHz. The electrode used for measurement was an open-ended
coaxial DAK-3.5 probe. The detail specifications of DAK-3.5 probe
are given in reference [36]. Before the collection of experimen-
tal data, the test fixture was calibrated using 3 standards; open
(air), short (copper strip), load (ecostock disc) to remove system-
atic measurement errors. The uncertainties of the measured high
frequency complex dielectric permittivity are within 4.0%.
To gain insights of relaxation mechanisms, the broadband di-
electric data were fitted to KWW [37] and HN [38] dielectric mod-
els using the LEVMW complex-nonlinear-least-squares computer
program [39]. The frequency domain complex dielectric function
can be well described by the KWW model through its numeri-
cal Fourier transformation [40]. In the present work, experimental
complex permittivity data could be well fitted to one-side Fourier
transforms KWW model. KWW model is also called a “stretched
exponential”, is given by [37]
  β 
t
ϕ (t ) = exp − (1)
τKW W
where, ϕ (t ) is the correlation function, τKW W is a characteristic
relaxation time and β is a stretched exponential parameter (0 <
J.B. Karakthala, H.P. Vankar and V.A. Rana
Table 1
Evaluation of different thermal effects observed from thermograph of DK.
Effect Onset, peak(◦ C) H(J/g)
a 69.39 12.92
b 273.97
c 299.27
−186.47
d 312.11
e 330.50
f 565.84 −8.68
β ≤ 1). The HN model was used to fit the experimental complex
permittivity data for each frequency ranges of measurement (i.e.,
20 Hz to 2 MHz, 200 MHz to 20 GHz). The general form of HN
model (including symmetric and asymmetric broadening of dielec-
tric relaxations) is given by Eq. (2) [38].
ε endothermic behaviour. Effect d shows the second stable phase at
ε ∗ (ω ) = ε  (ω ) − jε  (ω ) = ε∞ +  b
1 + ( jωτHN )a
where, ε∞ is the high frequency limit of real permittivity spec-
tra (ε  ), ε = εs − ε∞ is the dielectric strength, εs is the √static
permittivity at low frequency, j is the imaginary unit ( j = −1 ),
ω = 2π f is the angular frequency, f is the measurement frequency,
τHN is the characteristic relaxation time and a, b are symmetric
and asymmetric broadening parameters of dielectric loss peak, re-
spectively. In order to get better fitting experimental results, we
have carried out the numerical fitting of low and high-frequency
dielectric spectra, to the HN function with a constant phase ele-
ment (CPE) term that takes into account the conductive processes
[41,42].
ε −ϕ
ε ∗ (ω ) = ε  (ω ) − jε  (ω ) = ε∞ +   + U ( jω )
a b
1 + ( jωτHN )
where, U and ϕ are free parameters.
2.4. MD simulation
MD simulation of DK was performed using Schrödinger Ma-
terial Science Suite (MSS, version 2019-3) [43,44]. Total 500 DK
molecules were taken in a cubic box of dimension 58.8551 Å. In
present work, interaction of DK molecules/atoms/ions were char-
acterized through the OPLS3e force field, providing accurate bind-
ing affinity predictions [45]. This procedure consists of 20 ns
of Brownian dynamics at isothermal isobaric NPT ensemble at
300.15 K temperature and 1.03 atmospheric pressure, followed by
20 ps steps in total 103 interval [46]. NPT ensemble was employed
by setting the Nose-Hoover chain thermostat [47] and Martyna-
Tobias-Klein barostat method [48,49], and the relaxation times
were set to 1 ps and 2 ps respectively. The cut-off distance was
set to 9 Å. We performed MD simulation in the workflow using
Desmond module [50].
3. Results and discussion
3.1. Thermal effect analysis
DSC thermograph of DK for heating rate 20◦ C/min is shown in
Fig. 1(A). Details of different thermal effects (marked from a to
f) that takes place during temperature scan are given in Table 1.
As temperature increases, material may obtain enough freedom
to spontaneously arrange themselves resulting into the crystalline
form and is shown as effect a. Such behaviour was observed for
DFHNa (compound produced by the treatment of diclofenac with
NaOH) below 130 °C by M.E. Palomo et al. [51]. Crystallization gives
Journal of Molecular Structure 1284 (2023) 135410
Thermal effect
Cold crystallization onset
Melting of metastable phase onset
First stable phase of melting
Decomposition
Second stable phase of melting
Melting of stable phase offset
Decomposition
off heat, representing the exothermic process. Afterwards, there is
no change in heat flux over the temperature range of 90 °C to
250 °C. Effect b shows the onset of melting with metastable phase
in which the material undergoes a phase transition (melting). Ef-
fect c represent the first stable phase of melting at 299.27 °C with
(2) 312.11 °C with sharp endothermic melting behaviour, the enthalpy
of fusion ( H) is −186.47 J/g. The endothermic melting peak in
DSC study of DK was observed by Chime et al. [52] at 311.4 °C,
which is in good agreement with our result. In the present study
two melting peaks corresponding to temperatures of 299.27 °C and
312.11 °C are observed during the heating process. The multiple
melting phenomena occurs in a variety of materials [53–55] and is
mostly attributed to prolonged heat conditioning durations, higher
crystallization temperatures, DSC scanning rates, various crystal
types, impurities, etc. The appropriately sufficient low DSC scan-
ning rate of DK allows the observation of the splitting of the peak;
indeed, such an effect is observed. Two endothermic peaks can
also lead to the presence of two or more kinds of crystals [55].
Effect e is offset of stable melting phase. Thermal decomposition
takes place, as shown with effect f having broad exothermic peak
followed by the endothermic and exothermic peaks. The small
exothermic peak detected at low temperature (near 300.15 K), is
(3) owing to an effect of the inertia of the measurements.
According to the TGA profile of DK as shown in Fig. 1(B), the
initial weight of DK was 10.4265 mg (100%) and is found sta-
ble in the temperature range of 25–255 °C. Thereafter the TGA
thermogram shows continuous weight loss of DK up to 800 °C.
In the temperature range of 255 to 370◦ C (marked as step 1 re-
gion) the weight of DK reduces up to 8.8155 mg (84.55%), which
shows about 15.46% (1.6124 mg) of major weight loss of DK; and is
possibly associated to the decarboxylation of the diclofenac anion
[56]. The corresponding derivative thermogravimetry (DTG) and
heat flow analysis of DK shows sharp endothermic peak in the
temperature range of 280 to 315 °C. The similar decomposition
of DK in the range of 290 to 350 °C was reported by Fini et.al.
[56] It is noteworthy that the DSC and TGA profiles of DK in this
temperature range indicate the presence of both melting and de-
composition processes. In literature, the comparison of TGA with
DSC profiles of various diclofenac salts [57,58] in the temperature
range of endotherm associated with melting showed an apprecia-
ble weight loss. It can be hypothesized that the DK undergoes ther-
mal dissociation upon melting, forming both the initial acid and
base that evaporate and lead to the loss of weight [58]. In a re-
gion of step 2 (400 to 610 °C), the weight of DK decreases linearly
up to 7.1449 mg (68.53%) and the corresponding weight loss of DK
in this region is 14.23% (1.4831 mg). The weight of DK reduces up
to 6.4525 mg (61.89%) in a step 3 region (610 to 800 °C), and the
equivalent weight loss of DK in this region is 6.64% (0.6924 mg).
The weight loss of DK in steps 2 and 3 are possibly due to break-
ing apart of chemical bond, suggesting decomposition of DK.
Purity determination of active and inactive ingredients is an ab-
solute requirement for the preparation of pharmaceutical products
since undesirable impurities could have very serious consequences
[59,60]. Impurities in an organic compound depresses the melt-
3
J.B. Karakthala, H.P. Vankar and V.A. Rana Journal of Molecular Structure 1284 (2023) 135410

Fig. 1. Thermal profiles: (A) DSC thermograms of DK heated at 20 ◦ C/min in the temperature range of 25 ◦ C to 600 ◦ C.The temperature during fusion T f is plotted against
inverse of fraction melted (1/F) in inset of figure. (B) TGA thermograms of DK heated at 20 ◦ C/min in the temperature range of 25 ◦ C to 800 ◦ C.

ing point [61,62]. The correlation between melting point depres-
sion and the degree of impurities is described using the simplified
Van’t Hoff equation as below [17].
RTm2 1
T f = Tm − x2
Hf F Fig. 2 and 3 show the complex dielectric permittivity spec-
Where, T f is the temperature during fusion (liquidus tempera-
ture), Tm is melting temperature of pure substance, R is the gas
constant (8.314 J mol−1 K−1 ), H f is change of molar heat of fu-
sion of pure substance, x2 is mole fraction of impure substance in
the liquid phase and F is the fraction melted. The chemical purity
of DK can be determined through the F1 plot (see inset of Fig. 1(A)),
which represents the temperature of fusion (T f ) as a function of
the inverse fraction melted ( F1 ). The original data is shown in the
nonlinearized form. The linearization was achieved through cer-
tain thermodynamic considerations and with arithmetical simplifi-
cations of the Van’t Hoff law [63]. STARe evaluation thermal anal-
ysis software was used to estimate the purity of DK by measuring
the slope of T f versus F1 plot and its intersection on y-axis (see in-
set in Fig. 1(A)). The determined purity of DK is greater than 98%,
and thus the corresponding impurities are 1.995%.
3.2. Complex dielectric permittivity spectra
(4)
tra of DK pellet in low frequency range (20 Hz ≤ f ≤ 2 MHz)
and high frequency range (0.2 ≤ f ≤ 20 GHz), respectively. In the
frequency region below 100 Hz, when electric field is applied,
ions move towards the electrode/sample interface, forming electri-
cal double layer (EDL) at the interface causing polarization, called
as Electrode Polarization (EP) effect [64–66]. This is exhibited as
very large value of dielectric constant, of the order of ∼103 , and
a strong drop of conductivity towards low frequencies. The EP ef-
fect can be more accurately identified in the plot of imaginary part
of the complex AC conductivity, and is determined using relation
σ  ac = ωε0 ε  [34]. The frequency position, where σ  shows dip (i.e.
the ε  starts to show an increase with decrease in frequency) and
is denoted as fon (on condition of EP effect) at about 9.46 kHz
[35]. Another defining frequency position of EP effect in the low

4
J.B. Karakthala, H.P. Vankar and V.A. Rana
Fig. 2. Experimental complex dielectric permittivity (fitted with KWW model) displaying α and β relaxation and complex AC conductivity spectra in the frequency range
20 Hz to 2 MHz.
Fig. 3. Experimental complex dielectric permittivity spectra with dielectric constant
(red line) and dielectric loss (blue line) in high frequency range displaying δ and γ
relaxation which is fitted with KWW model.
frequency region is denoted as fmax at about 1.00 kHz in the σ 
plot of DK, which corresponds to the peak of σ  plot. The fmax
is the frequency position which suggests the full development of
electrode polarization [67]. AC conductivity σac , determined using
relation σac = ωε0 ε  [34], when plotted against frequency exhibits
a plateau in the frequency range higher than 1.5 kHz, as shown
in Fig. 2. The frequency independent plateau when extrapolated
to zero frequency provided the DC value of conductivity [68,69]
σdc = 0.316 × 10−6 S/m. Decrease in dielectric constant value up
to kHz frequency range is due to decreasing ability of ions to oscil-
late with frequency of the electric field [64]. Contribution of con-
ductivity to the dielectric permittivity can be well predicted by
Kramers-Kronig [70,71]. According to Kramers-Kronig the change
in conductivity is about 10−6 S/m for every 10 times increment of
permittivity in low frequency range while in high frequency range
change in conductivity is about some 10−3 S/m. It can be seen from
Fig. 2 that our result agrees with Kramers-Kronig findings.
5
Journal of Molecular Structure 1284 (2023) 135410
Primary (α ) and secondary (β , δ, γ ) relaxations are observed in
fitted data of dielectric loss spectra in low and high frequency in
KWW model and obtained relaxation time represents characteristic
relaxation time associated with respective relaxations. The low fre-
quency dielectric loss spectra (Fig. 2) reveal DC conductivity effect
associated with translational motions of potassium (K+ ) ions. Phar-
maceutical substances with low molecular weight exhibit a well
resolved structural α -relaxation peak in low frequency (100 Hz –
20 kHz) [72,73]. In the present case, such an α -relaxation peak
with relaxation time, τα = 0.119 ms, reflects reorientation of entire
DK molecules. This motion is thought to have a cooperative nature
since each molecule that reorients necessitates certain reorienta-
tions of neighbouring molecules. In the procedure of KWW fitting
of α -relaxation the stretched exponential function gives value, βα =
0.65 which confirmed that experimentally observed structural re-
laxation peak is asymmetric and broader than that for classical De-
bye response [74]. The α -relaxation peak has higher intensity than
all other secondary relaxation mechanism as can be seen in Fig. 2.
The β - relaxation is observed in intermediate frequency
(20 kHz – 2 MHz) with relaxation time, τβ = 0.369 μs (stretched
exponent, ββ = 0.50). β - relaxation originate from either inter or
intramolecular motions of DK molecule. Intramolecular motions re-
flects the movement involving only a subset of entire molecule,
called as non-JG (Johari-Goldstein) β -relaxation and intermolec-
ular motions originate from a small angle reorientation of the
entire molecule, called as JG β - relaxation [27]. In this mate-
rial, the dielectric loss peak related with the β -relaxations is de-
tected as an additional flank, so-called excess wings present in the
high frequency side of structural relaxation peak, it was suggested
that this phenomenon is associated with intermolecular motions
of molecules covered by dominating structural relaxation [75,76].
However, the identification of JG relaxation and other secondary
(non-JG) processes in dielectric spectra is of great importance and
often challenging for such tightly coupled structural and secondary
β processes. As a result, the extended coupling model (CM), de-
veloped by Ngai [77], has been suggested as a helpful criterion
for classifying secondary JG and non-JG processes. In this model,
the JG relaxation time (τJG ) is related to the structural relaxation
1−β
time as, τJG ≈ τ0 = (tc ) α β
(τα ) α , where τ0 is the primitive relax-
ation time, tc = 2 ps [73] is onset time of intermolecular coupling
for the small molecules, βα is the stretched exponential parameter
J.B. Karakthala, H.P. Vankar and V.A. Rana Journal of Molecular Structure 1284 (2023) 135410

Table 2
Fitted values of the dielectric relaxation parameters obtained using HN model without and with CPE term, for DK.† .

Dielectric Low frequency range High frequency range

parameters
HN fit HN + CPE fit HN fit HN + CPE fit

ε∞ 4.77 (0.97) 4.62 (1.52) 2.57 (0.74) 2.58 (0.86)

ε 915.08 (1.18) 779 (2.58) 3.67 (2.63) 3.52 (2.31)
τHN 0.281 ms (2.32) 0.312 ms (1.78) 0.595 ns (1.82) 0.559 ns (1.67)
a 0.79 (1.55) 0.96 (2.87) 0.93 (2.49) 0.95 (2.31)
b 0.98 (2.02) 0.95 (1.73) 0.99 (1.47) 0.98 (1.40)
U — 3.99 × 104 (1.82) — 3.68 × 104 (1.47)
ϕ — 0.99 (1.43) — 0.66 (2.04)
†
Relative standard deviation in percentage, as determined by CNLS fitting, is indicated in brackets. e.g., 4.77 (0.97) means 4.77 ± 0.97%.

of α -relaxation. The determined approximate value of τJG through

CM model is 0.227 μs and is evident that the JG relaxation antici-
pated by CM model lies quite close to the KWW fitted β -relaxation
time. Thus, the secondary β -relaxation process of DK can be classi-
fied as the JG process indicating a small angle reorientation of DK
molecule.
Secondary relaxations of rigid molecules are normally limited
to one and is of the JG kind. However, the secondary relaxation
of flexible molecules with internal degrees of freedom can possi-
bly be caused by a motion of small group or part of the molecule
and is faster than the JG relaxation [78,79]. In this study, bond
rotation led to different non-JG relaxation mechanisms. Non-JG δ -
relaxation (Fig. 3) lies in the high frequency range with relaxation
time, τδ = 0.267 ns (stretched exponent, βδ = 0.46), and com-
paratively its magnitude is small. The δ -relaxation occurs between
β and γ -relaxation. Another non-JG relaxation i.e., γ -relaxation
(Fig. 3) lies in high frequency range (1.5–20 GHz) with relaxation
time, τγ = 25.32 ps (stretched exponent, βγ = 0.50). The torsion
data of DK determined through MD simulation, as discussed in
Section 3.3, confirms that there are four rotatable bonds present
in the structure of DK. Among these bonds, the rotation of pheny- Fig. 4. Real (ε  ) and imaginary (ε  ) part of complex dielectric function for DK
showing fitting with Havriliak-Negami relaxation.
lacetic ring or chlorinated ring might be responsible for the exis-
tence of δ -relaxation process. The size of acetate anion and car-
boxylate anion are small as compared to the phenylacetic ring or region. Moreover, the comparison of CPE term of Eq. (3) to the con-
chlorinated ring in DK. Thus, the γ -relaxation can originate from ductivity term reported by Kassiba et al. [80] is found similar. i.e.
the rotation of such anion. −ϕ
U ( jω ) = σdc /iε0 ω and thus, σdc = U ε0 , where ε0 is the per-
The dielectric data recorded at low (20 Hz to 2 MHz) and high mittivity of vacuum. This equation is utilized to find the DC con-
(200 MHz to 20 GHz) frequency range was further analysed by ductivity value by accounting the fitted value of U as reported in
fitting it to the Havriliak-Negami function with and without CPE Table 2. The determined values of DC conductivity for low and high
term. Due to the limited number of data points available for β frequency region are 0.353 × 10−6 S/m and 0.326 × 10−6 S/m,
and γ -relaxation process, the α -relaxation (in low frequency re- respectively; which shows good agreement with the value of DC
gion) and δ -relaxation (in low frequency region) are taken into conductivity determined through the extrapolation method in AC
account in fitting procedure. The dielectric response of a mate- conductivity spectra. The complex dielectric data for intermediate
rial may be affected by the presence of mobile charges or ions. frequency region (2 MHz to 200 MHz) were also calculated using
Thus, an additional term (CPE) may be added to the HN func- HN model with CPE term, in which the high frequency fitted data
tion to account for the contribution of these charges to the dielec- reported in Table 2 were utilized. It is worth noticing that the cal-
tric response. The HN model is used for describing the dielectric culated complex dielectric data showed good agreement with the
response of materials only. The fitted HN model with CPE term low and high frequency experimental complex dielectric data, al-
provided good fitting to low (α -process) and high (δ -process) fre- though different experimental techniques were employed to mea-
quency spectra. Conductivity largely contributes to the experimen- sure the data in two frequency ranges.
tal dielectric permittivity spectra of DK bellow 100 Hz frequency.
Such contribution of conductivity is confirmed by employing the
3.3. Molecular dynamic simulation
HN model (eliminating CPE term in Eq. (3)) to low frequency di-
electric loss spectra (see Fig. 4). Fitted values of dielectric relax-
The MD simulation of DK containing 500 DK molecules in a cu-
ation parameters are presented in Table 2. In the low frequency
bic box, which is subjected to the conventional periodic bound-
region, the fitted data of dielectric strength ( ε ) and Havriliak-
ary conditions is shown in Fig. 5. MD simulation provided im-
Negami relaxation time (τHN ) for HN and HN + CPE model are
portant information of non-covalent bond interactions like hy-
found to be different. Conversely, the fitted data of DK through HN
drogen bonds, halogen bonds, salt bridge and aromatic H-bonds
and HN + CPE model in the high frequency region does not reveal
(as shown in Fig. 6); of which our main interest of research
any appreciable differences. Such behaviour of CPE term suggest
is, inter/intramolecular interaction via H-bond. An independently
that the contribution of conductivity or ions of material (DK) is
optimized geometrical monomer structure of DK obtained by
greater in low frequency region as compare to the high frequency
Schrödinger Material Science Suite is shown in Fig. 7. As can be

6
J.B. Karakthala, H.P. Vankar and V.A. Rana
Fig. 5. A representative microstructure of DK at 303.15 K in a cubic box of dimen-
sion 58.8551 Å.
seen from the figure, phenylacetic ring (aromatic benzene ring
with acetate ion) and chlorinated ring are found twisted at an an-
gle of 69.1° with respect to each other. A nearly similar angle (69°)
between the aromatic rings of diclofenac was found by Sallmann
[7] through its X-ray analysis. This mutual position (twist) of aro-
matic rings may be attributed to the repulsion between acetate an-
ion (−CH3 COO− ) and Cl atoms [6,7]. In addition, the torsion data
reported by Sallmann [7] for various modified diclofenac struc-
tures suggested that the torsion of chlorinated ring in diclofenac
increases with an increase in number of Cl atoms at the ortho po-
sition of phenyl ring; indeed, it can be said that the Cl atoms have
an impact on the twist of the aromatic rings in DK. Such arrange-
ment of DK molecule enables the specific interactions with the cy-
clooxygenase enzyme [6,81]. Further, the phenyl rings of DK pro-
vide a good fit in the substrate-binding pocket of the cyclooxyge-
nase resulting in increase of its inhibition activity [6,81,82]. How-
Fig. 6. Different inter and intra molecular interactions detected in MD simulation of DK.
7
Journal of Molecular Structure 1284 (2023) 135410
ever, the study of inhibition activity of diclofenac has suggested
that the existence of higher inhibition activity of diclofenac can
also depends on the basis of the existence of intramolecular hy-
drogen bonds, which stabilize significantly the drug structure in its
preferable, for COX-2 enzyme, configuration with maximum twist
between the phenyl rings [6].
The ligand torsion profile of DK over simulation time scale of
20 ns is shown in Fig. 8. A radial plot and a bar plot are used to
describe each of the rotatable bond torsions. These plots explain
the conformational evolution of the rotatable bonds in DK during
the simulation time. The probability density of each torsional rota-
tion is explained by the bar plot, and the radial plot displays the
torsion conformation as it was seen during the simulation time.
There are four rotatable bonds present in DK. First rotatable bond
is located between C7 and N5 atoms (sky blue), with torsion an-
gle of 144.71 to 179.97° (clockwise) and −135.46 to −179.97° (an-
ticlockwise); second is in between C6 and C8 atoms (green) hav-
ing torsion of −43.84 to −114.64°; third is in between C8 and C16
atoms (pink), with torsion angle of 14.01 to 177.74° and −7.18 to
−179.46°; and the fourth is among C9 and N5 atoms (orange) hav-
ing torsion range of 52.11 to 138.21° This torsion profile might shed
light on the conformational stress that the ligand experiences in
order to keep its conformation coupled to the protein [83].
3.3.1. Radial distribution function analysis
The radial distribution function (RDF) denoted by g(r) defines
the probability of finding particles at a distance r from another
tagged particle. The RDF is an effective parameter for systematic
investigation of the inter/intra molecular structure and molecu-
lar interaction in bulk system [84–86]. Thus, RDF of DK molecule
and its different configurated atoms were determined, which are
shown in Fig. 9. In present study, g(r) was determined up to
12 Å with an interval of 0.1 Å by means of its centre of mass.
The RDF plot of DK/DK pair molecules provides information about
the molecular arrangements and local binding behaviour of DK
molecule in reference to another DK molecules. In this plot, the
value of g(r) shows maxima at the radial distance of 4.2 Å, which
indicates the higher probability of DK/DK pair molecules in the
system [87]. To get the detail insights of inter/intra molecular in-
teraction of DK molecule at atomic level, the centre of mass RDF
for different configurated atomic pairs were determined. The RDF
of O/H atomic pair which include the overall oxygen and hydrogen
atoms presented in DK molecule shows initial two peaks, lower
J.B. Karakthala, H.P. Vankar and V.A. Rana Journal of Molecular Structure 1284 (2023) 135410

Fig. 7. 3-Dimensional independently optimized molecular structure of DK, suffix number of atoms signify the geometrical arrangement used in MD simulation; and blue
curved arrow represent the rotatable bonds.

Fig. 8. Ligand torsion profile of DK during the simulation trajectory of 20 ns. The rotation of colour coded rotatable bonds of DK are accomplished by a radial and bar plot,
in their respective colour. The clockwise and anticlockwise movement of the rotatable bonds are considered as positive and negative angle, respectively.

and higher peaks at radial distance of 3.2 and 4.3 Å respectively.
The value of g(r) for first peak is 0.52 and that of for second
peak is 1.85, which indicate that the probability to find O/H atomic
pair is low at radial distance of former peak. Further, it is notable
that the observed behaviour of RDF plot for O/H atomic pair in-
cludes both polar and nonpolar hydrogen atoms of DK. Thus, the
polar hydrogen atom of DK molecule might have significant role in
one of the peaks. To confirm this hypothesis, we have determined
centre of mass RDF for O/Hpolar , which includes the overall oxy-
gen atoms and polar hydrogen atoms of DK molecules. The RDF
plot of O/Hpolar display the first peak at radial distance of 3.0 Å
and corresponding value of g(r) is 2.37. Noteworthy, the radial dis-
tance of first peak position for O/Hpolar (3.0 Å) and O/H (3.2 Å)
atomic pairs are found closer, which indicate that the polar hydro-
gen atom plays a major role in the first peak (amorphous shell) of
O/H atomic pair in the system. Moreover, to identify the specific ef-
fect of oxygen atom associated to carboxylic group of DK molecule
in system, the RDF of O(3)/Hpolar and O(4)/Hpolar were determined.
The O(3)/Hpolar atomic pair involves oxygen which has 3rd atom
number and polar hydrogen atoms of DK, while O(4)/Hpolar atomic
pair involves oxygen which has 4th atom number and polar hy-
drogen atoms of DK. The RDF of O(3)/Hpolar and O(4)/Hpolar shows
two peaks in radial distance ranging from 0 to 4.5 Å. The first peak
position of O(3)/Hpolar and O(4)/Hpolar atomic pairs is 2.0 Å while
the second peak position of the same atomic pairs is 3.5 Å, which
shows that radial distance of first and second peak positions are

8
J.B. Karakthala, H.P. Vankar and V.A. Rana
Fig. 9. Radial Distribution Functions (RDF) plot for different atomic and molecular
pairs of DK.
Fig. 10. Running coordination numbers of different atomic and molecular pairs of
DK. Inset figure shows close view within radial distance of 5 Å.
identical. However, the radial distribution of both peaks are found
narrower for O(4)/Hpolar than O(3)/Hpolar , which indicate that the
oxygen atom allied to carbonyl group has more ordered local struc-
ture with respect to other polar H atoms [84]. Further, the higher
pick value of g(r) in O(4)/Hpolar than O(3)/Hpolar atomic pair indi-
cate that binding of local structure of O(4) atom allied to carbonyl
group around polar H atoms is significantly higher compare to the
binding of O(3) atom to polar H atoms.
3.3.2. Coordination numbers analysis
The coordination number indicates how many molecules are
found in the range of each coordination sphere. Integrating g(r)
from zero to the specified interatomic distance will give the run-
ning coordination numbers [88]. The characteristic running coor-
dination numbers for DK molecule and their different configu-
rated atomic pairs are shown in Fig. 10. The inset of this fig-
ure shows a close view of running coordination numbers rang-
ing from 1 to 5 Å. In depicted figure, the value of coordina-
tion numbers increases with increasing the radial distance be-
tween pair molecules/atoms. In molecular or structural arrange-
ment, the first amorphous/coordination shell and in some cases
second amorphous shell play crucial role. Thus, we have deter-
mined the coordination number for first/second amorphous shell
9
Journal of Molecular Structure 1284 (2023) 135410
Table 3
The coordination numbers of different configurated atomic and molec-
ular pairs in first and second amorphous shell.
Molecule/Atomic Coordination numbers
pairs
First amorphous Second amorphous
shell shell
DK/DK 3.15 —
O/H 0.12 1.4
O/Hpolar 1.15 —
O(3)/Hpolar 0.12 1.01
O(4)/Hpolar 0.14 1.02
by taking the integral boundary condition of centre of mass RDF
up to first/second minimum. The determined coordination num-
bers for different configurated molecule/atomic pairs are reported
in Table 3. Due to the higher radial distance of second amorphous
shell, only the coordination numbers of first amorphous shell of
DK/DK and O/Hpolar pairs were considered, which has the values
of 3.15 and 1.15 respectively. The coordination numbers of first and
second amorphous shell for O(4)/Hpolar atomic pair is found higher
than O(3)/Hpolar which confirms that structures of O(4) and polar
H atom are more ordered with higher binding affinity.
3.3.3. H-bond analysis
Tang et al. [89] studied the differences in the hydrogen bonding
tendencies of the crystalline and amorphous states through FTIR,
Raman spectroscopy, and single crystal X-ray data. It was con-
cluded that H-bond was stronger in some molecules of amorphous
and crystalline state. Thus, the authors further investigated the
temperature dependency of hydrogen bonding and discovered that
H-bond weakened significantly for T > Tg (glass transition tem-
perature) and T > Tm in amorphous and crystalline state, respec-
tively [14]. Such molecular interactions affected by molecular mo-
bility plays major role in predicting the physical stability of phar-
maceutical drug. For example, molecular mobility in the study of
acetaminophen, Gunawan et al. [90] pointed out that hydrogen
bond must be broken to diffuse the molecule followed by forma-
tion of new H-bonds between new molecules affecting the relax-
ation time. Whereas Bhugra et al. [14] suggested that, strength of
H-bonds in molecules may considerably impact the structural re-
laxation time, i.e., molecular mobility and hence effect the ten-
dency of crystallization. Molecular mobility varies rapidly with
temperature near and above Tg , which results in physical instabil-
ity. To overcome this problem, authors suggested that knowledge
of such interactions may be useful if certain donor or acceptor
(that we have studied in our system) groups are targeted by excip-
ients to disrupt H-bonds and achieve physical stability. Wang et al.
[91] prepared the highly stable DK by adding excipients in order to
form stable DK drug.
The DK structure has different proton donor and acceptor sites
allied to carboxylic and secondary amine group. Hence, the sys-
tematic investigation was carried out for all these sites in view of
H-bond interaction. Numbers of H-bonds detected as a function of
time for different proton donor and acceptor sites (O/H, O(3)/H,
O(4)/H and N/H) were evaluated from simulation event analysis
of Desmond and are presented in Fig. 11. In this plot, the H-bond
formation between overall oxygen and hydrogen atoms (O/H) are
higher than that of O(3)/H and O(4)/H atoms. The average H-bond
counts for O/H atoms are 102, which is nearly the summation of
the average H-bonds counts for O(3)/H and O(4)/H, i.e. 52 and
53 respectively. Interestingly, the H-bond counts between nitrogen
and hydrogen atoms (N/H) is zero throughout the time scale of
20 ns in the system. This observed behaviour indicate that nitro-
gen atom allied to secondary amine group is not acting as proton
acceptor site in the system. Further, the formation of H-bonds by
J.B. Karakthala, H.P. Vankar and V.A. Rana
Fig. 11. Number of H-bonds detected as a function of time for O/H, O(3)/H, O(4)/H and N/H atomic pairs.
considering different sites i.e. O/Hpolar and O/H(22) (oxygen atoms
and 22nd numbered hydrogen atom) were investigated and the av-
erage H-bond counts in both sites are same to the O/H site. These
results suggests that the hydrogen of secondary amine group (-NH)
is the only atom that forms the intra and inter molecular hydro-
gen bonds, see Fig. 6. Intramolecular H-bond forms when a pro-
ton donor and acceptor are in the same molecule, where polar
hydrogen of secondary amine group acts as a donor and oxygens
of carboxylic group acts as an acceptor; while intermolecular H-
bond form between the hydrogen of secondary amine group of one
molecule and oxygens of carboxylic group of another molecule. The
aromatic H-bond formed between the nonpolar hydrogen of aro-
matic benzene ring and oxygens of carboxylic group. It is a weaker
electrostatic interaction, is about half stronger than the H-bond
[92] and represented as a cyan dashed line in Fig. 6. Thus, the po-
larity of molecule has a great influence on the formation of hydro-
gen bond of various types and an indirect effect on the dielectric
constant and dipolar relaxation time [49,93,94].
4. Conclusions
In the present work, structural characteristics and the in-
ter/intra molecular interactions of a pharmaceutical drug molecule
viz. diclofenac potassium (DK) were investigated using broadband
dielectric spectroscopy (BDS) and molecular dynamic (MD) sim-
ulation at temperature of 300.15 K. Dielectric measurements for
DK over a broad frequency span covering two frequency ranges:
low frequency (20 Hz ≤ f ≤ 2 MHz) and high frequency (0.2 ≤
f ≤ 20 GHz) were taken. A variety of information is provided on
AC/DC conductivity behaviour, electrode polarization, primary α -
relaxation and secondary β , δ and γ -relaxation arising from dif-
ferent atomic/molecular/ionic response to an applied electric field.
Complex permittivity data of DK could be well fitted to two dielec-
tric functions: Kohlrausch–Williams–Watts (KWW) and Havriliak-
Negami (HN). The dielectric relaxation study of DK through dif-
ferent dielectric models showed relaxation processes like α , β , δ
and γ ; of which the primary structural α -relaxation originate from
reorientation of entire DK molecules, while secondary relaxations
(β , δ, γ ) are attributed to the inter/intra molecular movement of
DK. Analysis of β -relaxation through the coupling model and other
ancillary factors leads us to the conclusion that the β -relaxation is
the Johari-Goldstein (JG) secondary relaxation, and it results from
small angle reorientation of DK molecule. The other secondary re-
laxation processes (δ, γ ) are found non-JG type. The existence of
δ -relaxation is related to the rotation of phenylacetic ring or chlo-
10
Journal of Molecular Structure 1284 (2023) 135410
rinated ring, while the rotation of acetate anion or carboxylate an-
ion are responsible for the γ -relaxation. DSC thermogram revealed
two endothermic stable phases at 299.27 and 312.11 °C tempera-
tures. The DSC and TGA profiles suggest the melting and decom-
position of DK in the temperature range 280–315 °C. The melt-
ing temperature of DK is 312.11 °C. Purity of DK determined us-
ing Van’t Hoff’s equation is greater than 98%. The TGA profile of
DK in the temperature range of 25–800 °C reveals a weight loss of
about 61.89%. The major weight loss of DK is found about 15.46%
in the temperature range of 255–370 °C. the MD simulation study
provided detail information about the donor and acceptor sites of
DK molecules. The polar hydrogen atom of DK plays major role in
the first amorphous shell of O/H atomic pair in the system. The
oxygen atom, O(4) allied to carbonyl group has more ordered local
structure with respect to other polar H atoms. Further, the bind-
ing affinity of local structure for O(4) atom around polar H atoms
is significantly higher compare to the binding of O(3) atom to po-
lar H atoms in the system. The H-bond investigation of the sys-
tem indicate that the DK molecules form inter and intra molecular
H-bonds. The average H-bond counts for O/H atomic pair is the
summation of the average H bonds counts for O(3)/H and O(4)/H
atomic pairs in the system. The nitrogen atom allied to secondary
amine group does not act as proton acceptor site in the system.
Amongst all hydrogens of DK molecule, the hydrogen of secondary
amine group (-NH) is the only atom which form the inter and in-
tra molecular hydrogen bonds. Detailed information about the hy-
drogen bond interactions in DK molecules, provided in this study,
will be helpful to explain various drug performances including sol-
ubility, stability, dissolution, bioavailability lipophilicity, membrane
permeability and many pharmaceutical properties of the drug.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
CRediT authorship contribution statement
J.B. Karakthala: Methodology, Validation, Formal analysis, In-
vestigation, Data curation, Writing – original draft, Visualization.
H.P. Vankar: Methodology, Validation, Formal analysis, Investiga-
tion, Writing – review & editing, Data curation, Visualization. V.A.
Rana: Conceptualization, Methodology, Resources, Writing – re-
view & editing, Supervision, Funding acquisition.
J.B. Karakthala, H.P. Vankar and V.A. Rana
Data availability
Data will be made available on request.
Acknowledgements
Authors acknowledge the funding agency DST, New Delhi
for providing financial assistance, through DST - FIST projects
[SR/FST/PSI-0 01/20 06] and [SR/FST/PSI-198/2014]. Authors are also
thankful to UGC, New Delhi for DRS - SAP program grants [No.
F.530/10/DRS/2010(SAP-1)] and [No. F530/17/DRS-II/2018(SAP-1)].
The experimental facilities developed using these grants, were uti-
lized to carry out this work. Authors are also thankful to Prof. P.
N. Gajjar, Head, Department of Physics, University School of Sci-
ences, Gujarat University, Ahmedabad for his constant encourage-
ment. Authors are also grateful to Prof. V. K. Jain, Head (Retd.), De-
partment of Chemistry, University School of Sciences, Gujarat Uni-
versity, Ahmedabad for providing computational facility to carry
out MD simulation.
References
[1] M. Mehta, V. Ragoonanan, G.B. McKenna, R. Suryanarayanan, Correlation be-
tween molecular mobility and physical stability in pharmaceutical glasses,
Mol. Pharm. 13 (2016) 1267–1277.
[2] T.T.D. Tran, P.H.L. Tran, Molecular interactions in solid dispersions of poorly
water-soluble drugs, Pharmaceutics 12 (2020) 745.
[3] G. Szklarz, K. Adrjanowicz, M. Dulski, J. Knapik, M. Paluch, Dielectric relaxation
study at ambient and elevated pressure of the modeled lipophilic drug fenofi-
brate, J. Phys. Chem. B 120 (2016) 11298–11306.
[4] B.G. Katzung, S.B. Masters, A.J. Trevor, Basic and Clinical Pharmacology, ninth
ed., McGraw-Hill Book Co., New York, 2004.
[5] J.M. Derasari, V.B. Patel, Spectrophotometric determination of febuxostat and
diclofenac potassium in their combined dosage form by simultaneous equation
and first order derivative methods, Asian J. Res. Chem. 6 (2013) 968–972.
[6] M. Kozlowska, P. Rodziewicz, A. Kaczmarek-Kedziera, Structural stability of di-
clofenac vs. inhibition activity from ab initio molecular dynamics simulations.
Comparative study with ibuprofen and ketoprofen, Struct. Chem. 28 (2017)
999–1008.
[7] A.R. Sallmann, The history of diclofenac, Am. J. Med. 80 (1986) 29–33.
[8] R. Altman, B. Bosch, K. Brune, P. Patrignani, C. Young, Advances in NSAID de-
velopment: evolution of diclofenac products using pharmaceutical technology,
Drugs 75 (2015) 859–877.
[9] D. Kovala-Demertzi, Transition metal complexes of diclofenac with potentially
interesting anti-inflammatory activity, J. Inorg. Biochem. 79 (20 0 0) 153–157.
[10] K. Sahra, K. Dinar, A. Seridi, M. Kadri, Investigation on the inclusion of di-
clofenac with β -cyclodextrin: a molecular modeling approach, Struct. Chem.
26 (2015) 61–69.
[11] I.I. Krasnyuk, L.V. Ovsyannikova, O.I. Nikulina, A.V. Belyatskaya, Y. Kharitonov,
V.V. Grikh, L.A. Korol, Y.A. Obidchenko, A.N. Vorob’ev, Solubility of diclofenac
acid form from solid dispersions, Pharm. Chem. J. 48 (2015) 733–737.
[12] S. El-Sayed, K.H. Mahmoud, A.A. Fatah, A. Hassen, DSC, TGA and dielectric
properties of carboxymethyl cellulose/polyvinyl alcohol blends, Phys. B Con-
dens. Matter 406 (2011) 4068–4076.
[13] T. Chen, D.M. Oakley, Thermal analysis of proteins of pharmaceutical interest,
Thermochim. Acta 248 (1995) 229–244.
[14] C. Bhugra, M.J. Pikal, Role of thermodynamic, molecular, and kinetic factors in
crystallization from the amorphous state, J. Pharm. Sci. 97 (2008) 1329–1349.
[15] P.G. Royall, D.Q.M. Craig, C. Doherty, Characterisation of moisture uptake
effects on the glass transitional behaviour of an amorphous drug using
modulated temperature DSC, Int. J. Pharm. 192 (1999) 39–46, doi:10.1016/
S0378- 5173(99)00270- 7.
[16] Y. Aso, S. Yoshioka, J. Zhang, G. Zografi, Effect of water on the molecular
mobility of sucrose and poly (vinylpyrrolidone) in a colyophilized formula-
tion as measured by 13C-NMR relaxation time, Chem. Pharm. Bull. 50 (2002)
822–826.
[17] A.A. Van Dooren, B.W. Müller, Purity determinations of drugs with differential
scanning calorimetry (DSC)—a critical review, Int. J. Pharm. 20 (1984) 217–233.
[18] J.-.A. Bama, E. Dudognon, F. Affouard, Impact of low concentration of strongly
hydrogen-bonded water molecules on the dynamics of amorphous terfena-
dine: insights from molecular dynamics simulations and dielectric relaxation
spectroscopy, J. Phys. Chem. B 125 (2021) 11292–11307.
[19] A.S. El-Houssiny, A.A. Ward, D.M. Mostafa, S.L. Abd-El-Messieh, K.N. Abdel–
Nour, M.M. Darwish, W.A. Khalil, Drug–polymer interaction between glu-
cosamine sulfate and alginate nanoparticles: FTIR, DSC and dielectric spec-
troscopy studies, Adv. Nat. Sci. Nanosci. Nanotechnol. 7 (2016) 25014.
[20] K. Grzybowska, M. Rams-Baron, K. Łucak, A. Grzybowski, M. Paluch, Study of
thermal properties, molecular dynamics, and physical stability of etoricoxib
mixtures with octaacetylmaltose near the glass transition, Int. J. Mol. Sci. 23
(2022) 9794.
11
Journal of Molecular Structure 1284 (2023) 135410
[21] F. Farsaci, E. Tellone, A. Galtieri, S. Ficarra, Expanding the repertoire of dielec-
tric fractional models: a comprehensive development and functional applica-
tions to predict metabolic alterations in experimentally-inaccessible cells or
tissues, Fluids 3 (2018) 9.
[22] N. Nasir, M. Al Ahmad, Cells electrical characterization: dielectric properties,
mixture, and modeling theories, J. Eng. 2020 (2020) 1–17.
[23] R.T. Blakey, A.M. Morales-Partera, Microwave dielectric spectroscopy–a versa-
tile methodology for online, non-destructive food analysis, monitoring and
process control, Eng. Agric. Environ. Food. 9 (2016) 264–273.
[24] M. Wolf, R. Gulich, P. Lunkenheimer, A. Loidl, Relaxation dynamics of a protein
solution investigated by dielectric spectroscopy, Biochim. Biophys. Acta - Prot.
Proteom. 1824 (2012) 723–730, doi:10.1016/j.bbapap.2012.02.008.
[25] P. Mehrotra, B. Chatterjee, S. Sen, EM-wave biosensors: a review of RF, mi-
crowave, mm-wave and optical sensing, Sensors 19 (2019) 1013.
[26] S.L. Shamblin, B.C. Hancock, Y. Dupuis, M.J. Pikal, Interpretation of relaxation
time constants for amorphous pharmaceutical systems, J. Pharm. Sci. 89 (20 0 0)
417–427.
[27] J. Knapik-Kowalczuk, M. Rams-Baron, M. Paluch, Current research trends in
dielectric relaxation studies of amorphous pharmaceuticals: physical stability,
tautomerism, and the role of hydrogen bonding, TrAC Trends Anal. Chem. 134
(2020) 116097.
[28] K. Adrjanowicz, K. Kaminski, M. Paluch, P. Wlodarczyk, K. Grzybowska, Z. Woj-
narowska, L. Hawelek, W. Sawicki, P. Lepek, R. Lunio, Dielectric relaxation stud-
ies and dissolution behavior of amorphous verapamil hydrochloride, J. Pharm.
Sci. 99 (2010) 828–839.
[29] U. Perricone, M.R. Gulotta, J. Lombino, B. Parrino, S. Cascioferro, P. Diana, G. Cir-
rincione, A. Padova, An overview of recent molecular dynamics applications as
medicinal chemistry tools for the undruggable site challenge, Medchemcomm
9 (2018) 920–936.
[30] E. Dudognon, J.-.A. Bama, F. Affouard, Molecular mobility of terfenadine: inves-
tigation by dielectric relaxation spectroscopy and molecular dynamics simula-
tion, Mol. Pharm. 16 (2019) 4711–4724.
[31] T. Chan, D. Ouyang, Investigating the molecular dissolution process of binary
solid dispersions by molecular dynamics simulations, Asian J. Pharm. Sci. 13
(2018) 248–254.
[32] D.M. Walden, Y. Bundey, A. Jagarapu, V. Antontsev, K. Chakravarty, J. Varsh-
ney, Molecular simulation and statistical learning methods toward predicting
drug–polymer amorphous solid dispersion miscibility, stability, and formula-
tion design, Molecules 26 (2021) 182.
[33] S. Decherchi, A. Berteotti, G. Bottegoni, W. Rocchia, A. Cavalli, The ligand bind-
ing mechanism to purine nucleoside phosphorylase elucidated via molecular
dynamics and machine learning, Nat. Commun. 6 (2015) 1–10.
[34] H.P. Vankar, V.A. Rana, Electrode polarization and ionic conduction relaxation
in mixtures of 3-bromoanisole and 1-propanol in the frequency range of 20
Hz to 2 MHz at different temperatures, J. Mol. Liq. 254 (2018) 216–225.
[35] V.A. Rana, D.K. Barot, H.P. Vankar, T.R. Pandit, J.B. Karakthala, AC/DC
conductivity and dielectric relaxation behavior of ionic solutions of
1-butyl-3-methylimidazolium chloride in methanol, J. Mol. Liq. 296 (2019)
111804.
[36] DAK, Professional Handbook V2.4, Available online: https://speag.swiss/assets/
downloads/products/dak/free_downloads/AN_DAK-TL_Best%20Practices.pdf,
(n.d.).
[37] G. Williams, D.C. Watts, Non-symmetrical dielectric relaxation behaviour aris-
ing from a simple empirical decay function, Trans. Faraday Soc. 66 (1970)
80–85.
[38] S. Havriliak, S. Negami, A complex plane analysis of α -dispersions in some
polymer systems, J. Polym. Sci. Part C Polym. Symp. (1966) 99–117.
[39] J.R. Macdonald, LEVM/LEVMW-Manual-CNLS (Complex Nonlinear Least
Squares) immitance, inversion, and simulation fitting programs for WINDOWS
and MS-DOS, (n.d.). https://jrossmacdonald.com/jrm/wp-content/uploads/
LEVMMANUAL.pdf.
[40] K. Grzybowska, S. Capaccioli, M. Paluch, Recent developments in the exper-
imental investigations of relaxations in pharmaceuticals by dielectric tech-
niques at ambient and elevated pressure, Adv. Drug Deliv. Rev. 100 (2016)
158–182.
[41] J.R. Macdonald, Comparison and application of two methods for the least
squares analysis of immittance data, Solid State Ion. 58 (1992) 97–107.
[42] J.R. Macdonald, Some alternate models for nearly constant loss in conductive
systems, Phys. Rev. B 66 (2002) 64305.
[43] S. Release, 4: Materials Science Suite, Schrödinger, LLC, New York, NY, 2015
2015.
[44] User Mannual, Desmond Release, Schrodinger, 2019 n.d..
[45] G. Murray, Handbook of Materials Selection for Engineering Applications, CRC
Press, 1997.
[46] M.A.F. Afzal, A. Browning, A. Goldberg, M.D. Halls, J.L. Gavartin, T. Morisato,
T.F. Hughes, D.J. Giesen, J.E. Goose, High-throughput molecular dynamics sim-
ulations and validation of thermophysical properties of polymers, Chem-
Rxiv. Cambridge: Cambridge Open Engag. (2020) 1–20, doi:10.26434/chemrxiv.
12250229.v1.
[47] P.K. Patra, B. Bhattacharya, Nonergodicity of the Nose-Hoover chain thermostat
in computationally achievable time, Phys. Rev. E 90 (2014) 43304.
[48] C.H. Mehta, R. Narayan, G. Aithal, S. Pandiyan, P. Bhat, S. Dengale, A. Shah,
U.Y. Nayak, S. Garg, Molecular simulation driven experiment for formulation
of fixed dose combination of Darunavir and Ritonavir as anti-HIV nanosuspen-
sion, J. Mol. Liq. 293 (2019) 111469.
J.B. Karakthala, H.P. Vankar and V.A. Rana
[49] H.P. Vankar, V.A. Rana, S. Dey, H.D. Patel, V.K. Jain, Molecular interaction in
binary mixtures of 3-Bromoanisole and methanol: a microwave dielectric re-
laxation spectroscopy and molecular dynamic simulation study, J. Mol. Liq. 325
(2021) 115186.
[50] Desmond User Manual, Schrodinger, 2019.
[51] M.E. Palomo, M.P. Ballesteros, P. Frutos, Analysis of diclofenac sodium and
derivatives, J. Pharm. Biomed. Anal. 21 (1999) 83–94.
[52] S.A. Chime, A.A. Attama, P.F. Builders, G.C. Onunkwo, Sustained-release di-
clofenac potassium-loaded solid lipid microparticle based on solidified reverse
micellar solution: in vitro and in vivo evaluation, J. Microencapsul. 30 (2013)
335–345.
[53] P. Gabbott, P. Clarke, T. Mann, P. Royall, S. Shergill, A high-sensitivity, high-
-speed DSC technique: measurement of amorphous lactose, Am. Lab. 35 (2003)
17–23.
[54] P. Corradini, R. Napolitano, L. Oliva, V. Petraccone, B. Pirozzi, G. Guerra, A
possible structural interpretation of the two DSC melting peaks of isotactic
polypropylene in the α -modification, Die Makromol. Chem., Rapid Commun.
3 (1982) 753–756.
[55] J.-.Y. Wang, Y.-.J. Li, J.-.C. You, F.-.G. Bian, Relationship between localization of
PBSU in interlamellar/interfibrillar regimes and double peaks in DSC/SAXS in
its blend with PVDF, Chin. J. Polym. Sci. (2022) 1–11.
[56] A. Fini, M. Garuti, G. Fazio, J. Alvarez-Fuentes, M.A. Holgado, Diclofenac salts.
I. Fractal and thermal analysis of sodium and potassium diclofenac salts, J.
Pharm. Sci. 90 (2001) 2049–2057.
[57] A. Fini, G. Fazio, L. Benetti, V. Ghedini, Thermal analysis of some diclofenac
salts with alkyl and alkylhydroxy amines, Thermochim. Acta 464 (2007) 65–74.
[58] A. Fini, C. Cavallari, F. Ospitali, Diclofenac salts. V. Examples of polymorphism
among diclofenac salts with alkyl-hydroxy amines studied by DSC and HSM,
Pharmaceutics 2 (2010) 136–158.
[59] N. Rahman, S.N.H. Azmi, H.-.F. Wu, The importance of impurity analysis in
pharmaceutical products: an integrated approach, Accredit. Qual. Assur. 11
(2006) 69–74.
[60] S. Görög, The changing face of pharmaceutical analysis, TrAC Trends Anal.
Chem. 26 (2007) 12–17.
[61] D. Giron, C. Goldbronn, Place of DSC purity analysis in pharmaceutical devel-
opment, J. Therm. Anal. Calorim. 44 (1995) 217–251.
[62] E. Allen, The melting point of impure organic compounds, J. Chem. Educ. 19
(1942) 278.
[63] N.N. Salama, M.A. Mohammad, T.A. Fattah, Thermal behavior study and de-
composition kinetics of amisulpride under non-isothermal and isothermal con-
ditions, J. Therm. Anal. Calorim. 120 (2015) 953–958.
[64] K. Kothari, V. Ragoonanan, R. Suryanarayanan, Dielectric spectroscopy of small
molecule pharmaceuticals—effect of sample configuration, J. Pharm. Sci. 103
(2014) 3190–3196.
[65] S. Emmert, M. Wolf, R. Gulich, S. Krohns, S. Kastner, P. Lunkenheimer, A. Loidl,
Electrode polarization effects in broadband dielectric spectroscopy, Eur. Phys.
J. B 83 (2011) 157–165.
[66] J.L. Oncley, Studies of the dielectric properties of protein solutions. I. Carboxy-
hemoglobin1, 2, J. Am. Chem. Soc. 60 (1938) 1115–1123.
[67] M. Samet, V. Levchenko, G. Boiteux, G. Seytre, A. Kallel, A. Serghei, Electrode
polarization vs. Maxwell-Wagner-Sillars interfacial polarization in dielectric
spectra of materials: characteristic frequencies and scaling laws, J. Chem. Phys.
142 (2015) 194703.
[68] G. Yellaiah, T. Shekharam, K. Hadasa, M. Nagabhushanam, Low tempera-
ture DC conductivity, impedance spectroscopy and dielectric properties of Na
doped Cd0. 8Zn0. 2S semiconductor compounds, J. Alloys Compd. 609 (2014)
192–200.
[69] R.J. Sengwa, P. Dhatarwal, Predominantly chain segmental relaxation depen-
dent ionic conductivity of multiphase semicrystalline PVDF/PEO/LiClO4 solid
polymer electrolytes, Electrochim. Acta 338 (2020) 135890.
[70] K.R. Waters, M.S. Hughes, J. Mobley, J.G. Miller, Differential forms of the
Kramers-Kronig dispersion relations, IEEE Trans. Ultrason. Ferroelectr. Freq.
Control. 50 (2003) 68–76, doi:10.1109/TUFFC.2003.1176526.
[71] J.S. Toll, Causality and the dispersion relation: logical foundations, Phys. Rev.
104 (1956) 1760.
[72] J. Knapik-Kowalczuk, M. Rams-Baron, M. Paluch, Current research trends in
dielectric relaxation studies of amorphous pharmaceuticals: physical stability,
tautomerism, and the role of hydrogen bonding, TrAC Trends Anal. Chem. 134
(2021) 116097.
12
Journal of Molecular Structure 1284 (2023) 135410
[73] J. Knapik-Kowalczuk, Z. Wojnarowska, M. Rams-Baron, K. Jurkiewicz, J. Cieleck-
a-Piontek, K.L. Ngai, M. Paluch, Atorvastatin as a promising crystallization in-
hibitor of amorphous probucol: dielectric studies at ambient and elevated
pressure, Mol. Pharm. 14 (2017) 2670–2680.
[74] K. Adrjanowicz, Z. Wojnarowska, P. Wlodarczyk, K. Kaminski, M. Paluch, J. Maz-
galski, Molecular mobility in liquid and glassy states of Telmisartan (TEL) stud-
ied by broadband dielectric spectroscopy, Eur. J. Pharm. Sci. 38 (2009) 395–
404, doi:10.1016/j.ejps.20 09.09.0 09.
[75] G.P. Johari, K. Pathmanathan, An analysis for β -process in several molecular
glasses, J. Chem. Phys. 85 (1986) 6811–6812.
[76] P. Tripathi, Dielectric spectroscopy studies of low-disorder and low-
dimensional materials, (2016).
[77] K.L. Ngai, An extended coupling model description of the evolution of dynam-
ics with time in supercooled liquids and ionic conductors, J. Phys. Condens.
Matter 15 (2003) S1107.
[78] K.L. Ngai, M. Paluch, Classification of secondary relaxation in glass-formers
based on dynamic properties, J. Chem. Phys. 120 (2004) 857–873.
[79] J. Einfeldt, D. Meißner, A. Kwasniewski, Polymerdynamics of cellulose and
other polysaccharides in solid state-secondary dielectric relaxation processes,
Prog. Polym. Sci. 26 (2001) 1419–1472.
[80] A. Kassiba, M. Tabellout, S. Charpentier, N. Herlin, J.R. Emery, Conduction and
dielectric behaviour of SiC nano-sized materials, Solid State Commun. 115
(20 0 0) 389–393.
[81] P. Gund, T.Y. Shen, A model for the prostaglandin synthetase cyclooxygenation
site and its inhibition by antiinflammatory arylacetic acids, J. Med. Chem. 20
(1977) 1146–1152.
[82] J.R. Vane, Inhibition of prostaglandin biosynthesis as the mechanism of action
of aspirin-like drugs, Adv. Biosci. 9 (2014) 395–411.
[83] A. Vetrivel, S. Natchimuthu, V. Subramanian, R. Murugesan, High-throughput
virtual screening for a new class of antagonist targeting LasR of Pseudomonas
aeruginosa, ACS Omega 6 (2021) 18314–18324.
[84] O.W. Kgagodi, F. Mbaiwa, Molecular dynamics study of 2,2 -difurylmethane
and n-propanol binary mixture, J. Mol. Liq. 227 (2017) 366–372, doi:10.1016/j.
molliq.2016.10.128.
[85] R. Wang, J. Wang, Q. Song, The effect of Na+ and H2O on structural and
mechanical properties of coal gangue-based geopolymer: molecular dynamics
simulation and experimental study, Constr. Build. Mater. 268 (2021) 121081.
[86] S. Vchirawongkwin, V. Vchirawongkwin, Evaluation of molecular radial distri-
bution function and solvent-excluded volume with the numerical integration
of the union of spheres, Comput. Theor. Chem. 974 (2011) 26–30.
[87] J. Wang, H. Lin, F. Li, S. Li, S. An, J. Yuan, Concentration-dependent structure
of mixed NH4Cl and (NH4) 2SO4 aqueous solutions from the X-ray diffraction,
Raman spectroscopy and molecular dynamics simulations, J. Mol. Struct. 1185
(2019) 469–477.
[88] V.V. Chaban, Binary mixtures of novel sulfoxides and water: intermolecu-
lar structure, dynamic properties, thermodynamics, and cluster analysis, Phys.
Chem. Chem. Phys. 20 (2018) 23754–23761.
[89] X.C. Tang, M.J. Pikal, L.S. Taylor, The effect of temperature on hydrogen bonding
in crystalline and amorphous phases in dihydropyrine calcium channel block-
ers, Pharm. Res. 19 (2002) 484–490, doi:10.1023/A:1015199713635.
[90] L. Gunawan, G.P. Johari, R.M. Shanker, Structural relaxation of acetaminophen
glass, Pharm. Res. 23 (2006) 967–979.
[91] Y. Wang, H. Huang, C. Zhang, Y. Tang, J. Li, X. Tang, C. Cai, Preparation of
highly stable diclofenac potassium pellet with microcrystalline cellulose by
extrusion–spheronization, Asian J. Pharm. Sci. 8 (2013) 356–361, doi:10.1016/
j.ajps.2013.11.003.
[92] M. Levitt, M.F. Perutz, Aromatic rings act as hydrogen bond acceptors, J. Mol.
Biol. 201 (1988) 751–754.
[93] T.R. Griffiths, D.C. Pugh, Correlations among solvent polarity scales, dielectric
constant and dipole moment, and a means to reliable predictions of polar-
ity scale values from cu, Coord. Chem. Rev. 29 (1979) 129–211, doi:10.1016/
S0 010-8545(0 0)82109-8.
[94] V.A. Rana, T.R. Pandit, Dielectric spectroscopic and molecular dynamic study of
aqueous solutions of paracetamol, J. Mol. Liq. (2019) 111203.