Journal of Saudi Chemical Society (2020) 24, 474–483

King Saud University

Journal of Saudi Chemical Society

www.ksu.edu.sa
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ORIGINAL ARTICLE

Thermal properties of drug polymorphs: A case

study with felodipine form I and form IV
Wei Guo a,1, Congwei Li a,1, Pengfei Du a, Yalin Wang b, Shuangli Zhao a,
Jing Wang a,*, Caiqin Yang a,*

a
School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, PR China
b
Basic Medical College, Hebei Medical University, Shijiazhuang 050017, PR China

Received 24 February 2020; revised 3 April 2020; accepted 11 April 2020

Available online 18 April 2020

KEYWORDS Abstract Thermal decomposition kinetics and solution thermodynamics of two polymorphs,
Felodipine polymorphs; felodipine form I and form IV, were investigated. The thermal decomposition kinetics of the poly-
Thermal decomposition morphs, containing thermal decomposing mechanism and the kinetic parameters were studied
kinetics; under non-isothermal conditions using Popescu method, and the shelf life was simply calculated.
Solution thermodynamics; The results showed that nucleation and growth (n = 3/4) of Avremi–Erofeev equation is the most
Drug shelf life; probable mechanism function for form I, and the integral form is G(a) = [
ln(1
a)]3/4; while the
Polyamorphism Mample Powel law (n = 1) is the most probable mechanism function for form IV, corresponding to
G(a) = a. Notably, the individual amorphous phases of crystal felodipine form I and IV were
obtained after the heating–cooling cycle of DSC tests, which were identified by TMDSC and FT-
IR measurements. As the interim products before the collapse, it can be inferred that different
amorphous intermediates may be the determinant for different thermal decomposition mechanisms
of crystal forms I and IV. The solubility data and solution thermodynamic parameters, including
enthalpy, entropy and Gibbs free energy have also been calculated by Van’t Hoff equation in etha-
nol aqueous. The results illustrated the polymorphic pair is enantiotropic with the transition tem-
perature of 322.23 K and the conversion is driven by entropy.
Ó 2020 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding authors. 1. Introduction

E-mail addresses: jingwang@home.ipe.ac.cn (J. Wang), yangcaiqin@-
hebmu.edu.cn (C. Yang).
1 crystallize with different arrangements or conformations in lat-
Both authors have contributed equally.
Peer review under responsibility of King Saud University.
Production and hosting by Elsevier
An increasing number of researches have demonstrated that
solid phases containing the same chemical composition may
tice, a phenomenon named polymorphism [1,2], which is extre-
mely common for active pharmaceutical ingredients. As is well
known, the polymorphs usually differ in physicochemical
properties, such as melting point, solubility, dissolution rate
and stability [3–5], which are exactly the main factors affecting

https://doi.org/10.1016/j.jscs.2020.04.003
1319-6103 Ó 2020 The Author(s). Published by Elsevier B.V. on behalf of King Saud University.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Thermal properties of drug polymorphs: A case study with felodipine form I and form IV 475

drug development and performance [6]. For instance, the poly-

morphic forms of same drug may show diverse bioavailabili-
ties, and even leading to different therapeutic effects in
clinical practice. Moreover, excessive inefficient polymorphous
component will invalidate the medication. Even worse, in the
extreme case, an undesired polymorph can even be toxic [7].
Consequently, the researches of pharmaceutical polymor- Scheme 1 The molecular structure of felodipine.
phism, such as screening and identification, stabilities, kinetics,
and transformation behaviors, were and will remain an impor-
tant topic in the development of new drugs, and helpful to con-
used for the characterization of heat exchange during phase
trol the stability of the crystalline drugs in the preparation and
transition, chemical reaction, absorption, mixing or similar
storage process.
activity for its several advantages such as save time, use less
Felodipine (ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihy
samples and operate simply. TG analysis is a main thermal
dro-2,6-dimethyl-3,5- pyridinedicarboxylate, see Scheme 1),
analysis approach used to examine thermal stability of materi-
one of dihydropyridine calcium channel blocker agents, shows
als. Determine kinetic parameters by TG is an important tool
evident advantage in vascular selectivity and lowering of
for estimating thermal decomposition kinetics. There are many
peripheral circulatory resistance and blood pressure [8]. To
kinetic methods for analyzing non-isothermal solid kinetic
date, four polymorphs of felodipine designated as form I, II,
data from TG curves. These methods can be divided into
III and IV were reported, whereas form I is used as the mar-
two types: model-fitting and model-free method. Application
keted products. Among these, form IV is the last repeatable
of model-fitting methods for non-isothermal data gives higher
and large-scale prepared one. Bauer-Brandl [9] and Yang [10]
values for kinetic parameters [23]. This method has recently
groups have reported some thermodynamic properties of
declined in favour of model-free method, the advantage of
forms I-IV, however, the systemic investigation of felodipine
which is founded on its simplicity and the avoidance of errors
polymorphs on thermal decomposition kinetics and solution
connected with the choice of a kinetic model [24]. On the other
thermodynamics has not been found in the literature.
hands, because many mechanisms of reactions are very often
Thermal properties of drugs to be developed, which may
unknown or too complicated to be described, isoconversional
determine the production process, storage conditions, trans-
methods, which allow determining the kinetic parameters with-
portation requirements, shelf life, bioavailability and so on,
out understanding of the actual mechanism, are often used to
are one of the most important techniques and the domains
describe their kinetics. Furthermore, isoconversional methods
of application in relation to critical steps in drug development
do not require any assumption on the reaction model, which
[11,12]. Based on this, thermal analyses have been widely used
is beneficial for avoiding possible errors associated with a
in pharmaceutical industry, from the choice of the active ingre-
wrong selection [25–27]. Based on this, many expressions,
dient to the drug product launch, including but not limited to
including the Kissinger equation [28], Ozawa equation [29],
the formulation design and development of drugs, the study of
and Popescu equation [30], are used to calculate the kinetic
drug stability and thermokinetics, and even the interactions
parameters of a solid state reaction without knowing the reac-
between drugs and biological organism [13,14]. Especially in
tion mechanism. Among these, Popescu analysis is a multiple
cases involving polymorphous and amorphous forms, their
scan rate method that requires analysis of multiple TG curves
solid forms can be directly influenced by solvent medium and
measured at different heating rates. The main advantage of
additional energy supply, such as heat or mechanical stress.
this method is that it neither includes any assumption concern-
Thus, measurements of thermodynamic features of drug sub-
ing the temperature integral, nor takes the rate constant into
stance, such as Gibbs free energy, enthalpy, entropy and
account, leading to the result with a higher precision [31].
enthalpy relationships, so that accurate assessment of the
Besides, this method allows the activation energy to be deter-
phase conversion behavior and then determining thermody-
mined as a function of the extent of conversion and/or temper-
namically stable solid form, is of critical importance and ben-
ature without making any deduction about the reaction model
efit for selection of the desired crystalline modification of the
[32]. On the other side, the stability of drug and its dosage is
drug [15,16]. Kinetics analysis uses many different processing
vital to determine the efficient storage duration. Traditional
methods to analyze the data determined by thermal analysis,
methods are really time consuming. By virtue of the kinetic
so as to not only obtain the kinetic triplet (activation energy,
parameters, shelf life of drugs can be predicted through a sim-
pre-exponential factor, and mathematical reaction mechanism)
ple way.
as theoretical application; but also can establish the quantita-
In this regard, we have initiated investigations of thermal
tive relationship between temperature, time, and reaction
decomposition kinetics and solution thermodynamics of
degree in practical. In the field of drug research, the kinetics
felodipine polymorphous form I and IV. The kinetic triplet,
can be used to study drug stability, predict the storage condi-
containing the activation energy Ea, pre-exponential factor A
tions and shelf life, as well as body metabolism [17,18].
and the most probable kinetic model were calculated using
Thermoanalytical techniques such as thermogravimetric
the Popescu equation. Meanwhile, the changes of thermody-
(TG) analysis, differential scanning calorimeter (DSC) and
namic parameters such as free energy, entropy and enthalpy
their combinations, have been commonly used to explore the
were calculated. This work provides a deep insight into the
heating/cooling behaviors and properties including melting
thermal decomposition and thermodynamic stability between
temperature, crystal identification, phase transition, purity
felodipine forms I and IV, and offers theoretical support for
determination or compositional analysis, thermal stability
preparation, process optimization and quality control of poly-
and thermal decomposition procedure of various industrial,
morphous drug formulations.
energetic and biological materials [19–22]. DSC approach is
476
2. Experimental
2.1. Materials
Felodipine was purchased from Shanghai Tong Yuan Chemi-
cal Co. (China) and presents polymorphic form I (>99.0%).
All other reagents and solvents (analytical grade) for the crys-
tal conversion and analysis were commercially available and
used without further purification.
The bulk crystal sample of felodipine form IV was prepared
by conversion of form I in basic methanol aqueous according
to the literature method [10]. Amorphous felodipine of form I
and IV were obtained by conversion of the corresponding crys-
tal polymorph after the heating–cooling cycle of DSC tests.
2.2. Characterization
Powder X-ray diffraction (PXRD) patterns of crystal samples
were collected on a Bruker D8 advance X-ray diffractometer
(Bruker, Germany) at 40 kV, 150 mA for Cu Ka radiation
(k = 1.5406 Å). The simulation of the PXRD patterns of crys-
talline felodipine form I and IV was performed by the single-
crystal data (obtained from the Cambridge Structural Data-
base with CCDC No. 1144174 and 864027, respectively) and
diffraction-crystal module of Mercury program. Differential
scanning calorimetry (DSC) was carried out on a NETZSCH
DSC 214 instrument equipped with a refrigerated cooling
accessory (IC40). Before tests, the instrument was calibrated
by employing pure indium (99.999%) metal. Nitrogen was
used as the purging gas with flow rate of 40 mLmin
1.
5~6 mg samples were heated from 30 to 200 °C at a heating
rate of 10 Kmin
1. The temperature modulated differential
scanning calorimetry (TMDSC) programs using the same
instrument were modulated at 0.5 K every 60 s with a heating
rate of 2 Kmin
1. Thermogravimetry (TG) and derivative
thermogravimetric (DTG) analysis were performed on a
NETZSCH TG 209 F3 thermogravimetric analyzer and the
nitrogen with a flow speed of 40 mLmin
1 was used as protec-
tive gas. All TG experiments were implemented from 30 to
450 °C with heating rates of 5, 10, 15, 20 Kmin
1, respectively.
Fourier transform infrared (FT-IR) spectra were scanned in
the range of 4000–400 cm
1 using an EQUINOX 55 (Bruker,
Germany) FT-IR spectrometer with KBr pellet.
2.3. Thermal decomposition kinetics of felodipine polymorphs
Popescu equations used are as follows:
Z an
da
GðaÞmn ¼ ð1Þ
am fðaÞ
Z Tn
IðTÞmn ¼ kðTÞdT ð2Þ
Tm
1
GðaÞmn ¼ IðTÞmn ð3Þ
b Ltd., Shanghai, China) for 36 h for equilibrium. The concen-
where T is the temperature (K), am and an are two different
degrees of conversion correspond to temperatures of Tm and
Tn, f(a) and G(a) are differential and integral mechanism func-
W. Guo et al.
tion of conversion degree a, k(T) is the temperature depen-
dence of the rate constant, b is the heating rate.
It has to be assumed that over certain ranges of a and b val-
ues, the kinetics of the reaction does not changed. For exam-
ple, the analytical forms of f(a) and k(T), consequently G
(a)mn and I(T)mn, are not changed when either a or b is varied.
According to the experimental results, when T equals Tm and
Tn, a pair of a values, (am1, an1), (am2, an2), . . ., (ami, ani) will
be determined under the different b. By virtue of these pairs
and various conversion functions [33], the values of G(a)mn1,
G(a)mn2, . . . , G(a)mni could be calculated based on equation
(1). Then for every conversion function G(a), the correspond-
ing values were obtained. As the temperature Tm and Tn were
the same at the different b, according to equation (2), it fol-
lowed that I(T)mn was a constant, and from equation (3), a plot
of the values of G(a)mn versus 1/b will lead to a straight line if
the analytical form of G(a) was properly selected. Further, the
function corresponding to the line with the best linear correla-
tion coefficient (r) and the intercept (b) close to 0, will be con-
sidered as the probable mechanism function of a solid phase
reaction [31,32]. Thus, equation (3) is actually the basis of
the method for finding the most probable kinetic mechanism
of the studied reaction.
The activation energy (Ea) and pre-exponential factor (A)
are calculated via follow equation:
   
b Ea A
ln ¼
þ ln ð4Þ
Tn
Tm RTn GðaÞmn
where Tn = (Tn + Tm)/2.
By substituting the values of (Tm1, Tn1), (Tm2, Tn2), . . .,
(Tmi, Tni) and the mechanism functions G(a)mn into equation
(4), the kinetic parameters of Ea, A and linear correlation coef-
ficients r were obtained by the linear least squares method with
ln[b/(Tn
Tm)] versus 1/Tn.
2.4. Drug shelf life
Generally speaking, the content of the drug is reduced more or
less during storage, and even lose its potency because of the
occurrence of oxidation and/or hydrolysis reaction. Studies
revealed the thermal decomposition reaction rate constant k
of solid state drug relates to storage temperature T via the
Arrhenius equation: k = Aexp(
Ea/RT). According to drug
pk (negative logarithm of rate constant k) value and the regu-
lation of drugs storage period of the correlation value, in stor-
age temperature (room temperature of 25 °C), drug shelf life is
1.5–2 years in the pk < 7.5, for 3 years in the 7.5 < pk < 10.5,
and for 4–5 years once the pk > 10.5 [18].
2.5. Solubility
The solubilities of forms I and IV felodipine in 20% ethanol
aqueous were determined at 25, 28, 31, 37, 42 and 52 °C using
the shake-flask method. An excess amount of each sample
(form I, IV) was placed in a 50 mL erlenmeyer flask with
30 mL solvent. Then the sealed flasks were shaken at
100 rpm in a SPH-200B air-bath shaker (Shiping Tech. Co.,
tration of felodipine in solvent was measured using an UV-
160A spectrophotometer (Shimadzu Co., Japan) at 365 nm
after filtering through a 0.45 lm membrane filter. All samples
Thermal properties of drug polymorphs: A case study with felodipine form I and form IV 477

were tested thrice. The standard calibration curve obtained

using the same method was as follows:
A = 0.0178q + 0.0025 (r = 0.9997, Beer’s law limit: 2.08–1
2.48 lgmL
1, LOD = 0.22, LOQ = 0.71).

2.6. Phase transition temperature and thermodynamics

As a water-insoluble drug [34], felodipine can be approxi-

mately regarded c (solubility) equals to a (activity) in an infi-
nitely diluted solution. According to the Van’t Hoff equation:
DH
ln c ¼
þ Const ð5Þ
RT
where c is solubility and 4H is the solution enthalpy.
According to equation (5), the lines were drawn with lnc as
the Y-coordinate versus 1/T as the abscissa for the two poly-
morphs, the values of 4H for form I and IV can be readily cal-
culated from the slope, and the temperature corresponding to
the intersection point of the two curves is the transition tem-
perature Tt [35,36]. Fig. 1 The simulated and experimental PXRD patterns of
Combine Gibbs–Helmholtz equation: felodipine crystalline form I and IV (a: simulated form I; b:
DGI;IV ¼ DHI;IV
TDSI;IV ð6Þ measured form I; c: simulated form IV and d: measured form IV).

where 4GI,IV, 4HI,IV and 4SI,IV are the Gibbs free energy
change, enthalpy change and entropy change of phase transi-
tion of the two polymorphs I and IV.
when cI = cIV, 4GI, IV = 0, then
DHI;IV ¼ Tt DSI;IV ð7Þ
where 4HI, IV = 4HI
4HIV, T = Tt, therefore, we get the
value of 4SI, IV.
when the temperature changes little, the 4HI,IV and 4SI,IV
of the system can be considered as fixed values, as such, the
value of 4GI, IV can be calculated at different temperatures
according to equation (6).

3. Results and discussion

3.1. Identification of felodipine form IV

Since the felodipine crystal form IV was transformed from

form I in solution, the formation of form IV were confirmed
by PXRD, FT-IR and DSC techniques, along with form I as
reference phase.
The simulated and experimental PXRD patterns of crys-
talline felodipine form I and IV are shown in Fig. 1. Obviously,
the peaks of new phase were apparently different from those of
the starting form, thereby suggesting the form I has completely
conversed. Furthermore, the pattern of new form is in good
agreement with that of simulated one of form IV (derived from
crystal structures [9]), confirming the corresponding bulk sam-
ple presented as felodipine form IV and in high phase purity.
Additionally, the FT-IR measurements revealed that the
spectral characteristics of obtained sample form IV were con-
sistent with those reported previously, verifying that the con-
verted product was form IV [10]. As shown in Fig. 2, N–H
stretching peak of 3372 cm
1 for form I shifts to 3329 cm
1
in form IV, and the C=O stretching vibrations provide addi-
tional information. For form I, the C=O peak is at
1698 cm
1, while for form IV, two C=O peaks can be
observed at 1703 and 1654 cm
1. All the spectral characteris-
Fig. 2 FT-IR spectra of felodipine crystalline form I (black) and
IV (red).
tics are consistent with the structural data, which further con-
firms the formation of form IV.
The thermal behaviors of felodipine crystalline form I and
IV were investigated by DSC with heating and cooling circle.
As can be seen from Fig. 3, the DSC curves of felodipine form
I and form IV show sharp and narrow endothermic peak at the
temperature of 148.2 °C (DHfusion = 77.01 Jg
1) and 151.5 °C
(DHfusion = 69.84 Jg
1), respectively. Surprisingly, on cooling
of the melted form I and IV, neither thermogram exhibits any
thermal activity indicating phase transformation. Accordingly,
it might be reasonable to speculate that crystalline form I and
IV become amorphous forms (represented by amI and amIV,
respectively) after melting. To test this deduction and explore
the differences of amorphization between the polymorphs,
TMDSC and FT-IR analysis were applied to characterize the
two amorphous forms of felodipine subsequently.
478
Fig. 3 DSC traces of crystalline felodipine from I and IV.
3.2. Characterization of amorphous forms of felodipine
The DSC technique is capable of only measuring the total heat
flow, and TMDSC based on it not only provides the total heat
flow, but even splits the DSC signal into non-reversible heat
flow and reversible heat flow simultaneously [37]. Generally
speaking, the non-reversible processes contains enthalpy
recovery, crystallization phenomena, and decomposition. Cor-
respondingly, reversible signals characterized heat capacity
(Cp) and glass transition procedures. TMDSC, for its high sen-
sitivity and resolution, has been used to measure the weak
glass transition temperature (Tg), the characteristic of amor-
phous matter, in lyophilized solutions [38,39], to separate ther-
mal events [40] and analyze enantiotropically-related
polymorphic transitions of furosemide in formulation studies
[41]. The heat capacity and Tg of amI and amIV were mea-
sured by TMDSC technique. As shown in Fig. 4, clearly, the
Tg location with values of 45.8 and 45.5 °C were observed
for samples of amI and amIV, respectively. This result con-
Fig. 4 TMDSC curves of amorphous felodipine amI and amIV.
W. Guo et al.
firmed the amorphous phases of amI and amIV. From the
numerical point of view, there is no significant difference in
the Tg between the two polyamorphism. However, the 4Cp
values for amorphous amI and amIV are 0.314 and 0.257 J(
gK)
1, being slightly different. However, there are many fac-
tors, typically such as the microstructure and intermolecular
interactions of material, are related to the heat capacity.
Accordingly, whether there is any difference between the two
amorphous microstructures cannot be determined just by
value of heat capacity. FT-IR spectrum is an effective analysis
method for the microstructure of molecule.
The FT-IR spectra of amorphous forms were presented in
Fig. 5. For both of amI and amIV, the broad band centered
at ca. 3340 cm
1 can be considered to arise from N–H stretch-
ing vibration. Meanwhile, the double peaks at 1700 and
1684 cm
1 can be assigned to C=O stretching vibration of
the amorphous phases, respectively for amI and amIV [42].
On the other side, by comparing of FT-IR spectra of amIV
and amI, although there are no obvious distinction in the
peaks of N–H and C=O stretching vibration, the different
absorption bands in 2850–3000, 1400–1600 cm
1 regions arise
from the vibrations of the aliphatic groups, for example, C–H
stretching peaks at 2981, 2947, 1490 cm
1 for amorphous amI,
and 2919, 2850, 1464 cm
1 in amIV are observed. These facts
may be used to prove the different atom location confused
degrees between the two amorphous and play an important
role to support their different conformations [43]. This result
suggests that the amorphous amI and amIV respectively con-
versed from crystalline forms I and IV are two kinds of sub-
stances with different microstructures. Meanwhile,
connecting the values of 4Cp as mentioned above, they should
be authentically different for different species.
3.3. Thermal decomposition kinetics of form I and form IV
The TG/DTG curves (b = 10 Kmin
1) of felodipine form I
and form IV are shown in Fig. 6. The TG curves of felodipine
polymorphs were relatively steep, and no significant continu-
ous weight loss step was observed in the heating progress.
The total weight loss rate of thermal decomposition was close
to 100%. With that, decomposition temperatures were minor
Fig. 5 FT-IR spectra of amorphous amI (black) and amIV (red).
Thermal properties of drug polymorphs: A case study with felodipine form I and form IV 479

(a)
Fig. 6 TG/DTG curves of form I and IV (black line: form I, red
line: form IV).

different, that is, 239. 5 °C for form I, and 245.1 °C for form
IV. Moreover, each DTG curve showed a single peak also indi-
cating decomposition process of form I and IV was one step
but presented a clear distinction between the two decomposi-
tion procedures. The DTG curves of form I had a strong
and sharp peak at 307.9 °C, meaning that decomposition rate
reached the maximum, while, in the case of form IV, the DTG
curve showed a sharp peak at 290.9 °C. Notably, comprehen-
sive analysis of DSC and TG results of crystal forms, with
regard to the TG curves (see Fig. 6), there is no weight loss
observed at least before 200 °C, but a sharp endothermic peak
appeared at each DSC trace of forms I and IV at ca. 150 °C,
indicating the melting of the crystal (see Fig. 3). Furthermore,
there is no thermal phenomena observed upon the cooling pro-
cedure for both samples. Combined the FT-IR comparison of
(b)
amI and amIV stated above, all these results can confirm that Fig. 7 TG curves for felodipine crystalline form I (a) and form
it is just a phase conversion from crystalline to amorphous IV (b).
phases but no decomposition occurs, more precisely, felodipine
polymorphs I and IV changed to polyamorphous amI and
amIV, respectively. IV, corresponding to G(a) = a. Combined the previous discus-
sion of DSC, TG and FT-IR spectra, the different species amI
3.4. Calculation of the kinetic triplet and drug shelf life and amIV, generated in the time between melting and decom-
position, can be regarded as the respective intermediate states
The TG curves of form I and IV at different heating rates of 5, of crystalline I and IV from raw material to thermal decompo-
10, 15, and 20 Kmin
1 are presented in Fig. 7. By substituting sition. The different intermediate states may cause change of
the corresponding conversion degrees at different Tm, Tn and reaction mechanism. Therefore, the different amorphous inter-
40 kinds mechanism function [33] into equation (1), respec- mediate states amI and amIV can be considered as the determi-
tively, the values of G(a)mn at different heating rates for every nant for the different decomposition mechanism of
conversion function were obtained. Plotting G(a)mn versus 1/b polymorphous forms I and IV.
and applying the linear least squares method, linear correlation The ln[b/(Tn
Tm)] versus 1/Tn linear regression equations
r and the intercept b were calculated. The selected linear fitting for forms I and IV were listed in Table 3. As seen in Table 4,
results of kinetic mechanism functions were listed in Tables 1 the value of Ea,I invariably lower than that of Ea,IV, this result
and 2. It can be seen that the data of No.15 for form I and implies that the energy barrier of the thermal decomposition of
No.25 for form IV, which are highlighted in bold, are the best, the form I was easily overcome, that is form IV is more stable
corresponding the correlation coefficient r was nearest to 1 and than form I in solid state. It also can be observed that the val-
the intercept b approached 0. Therefore, nucleation and ues of Ea and A for form I and IV obtained from Popescu
growth (n = 3/4) of Avremi–Erofeev equation is the most method are consistent basically with the values calculated by
probable mechanism function for form I, and the integral form the Ozawa and Kissinger methods, and these methods verify
is G(a) = [
ln(1
a)]3/4; meanwhile, Mample Powel law each other to increase the accuracy of the results. Combination
(n = 1) is the most probable mechanism function for form with the TG and DSC results, when continuous heating,
480 W. Guo et al.

Table 1 Selected linear fitting results of kinetic mechanism functions for form I.
Mechanism code Tm (Tn)/K
563.85 (566.55) 566.55 (570.65) 570.65 (572.95) 566.55 (577.35) 577.35 (581.35)
b r b r b r b r b R
1
0.0167 0.9978
0.0052 0.9990
0.0358 0.9991
0.0807 0.9959
0.0210 0.9545
6
0.0056 0.9854
0.0026 0.9961
0.0130 0.9779
0.0363 0.9869
0.0300 0.9844
11 0.0125 0.9742 0.0267 0.4381
0.0059 0.9904 0.0482 0.9997 0.0030 0.9928
15
0.0050 0.9967 0.0175 0.9991
0.0312 0.9994
0.0486 0.9986 0.0527 0.9992
17
0.0452 0.9932
0.0203 0.9977
0.1334 0.9907 0.3730 0.9883
0.2884 0.9872
20 0.0776 0.9599
0.0748 0.9631
0.4480 0.9582
1.9711 0.9569
3.3864 0.9556
25 0.0017 0.9871 0.0171 0.9619 0.0023 0.9849 0.0285 0.9868 0.0133 0.8907
35 0.0679 0.9916 0.02990 0.9939
0.2444 0.9961
0.7758 0.9808
0.8661 0.9740
39 0.2368 0.2128 0.3285 0.9058 0.2484 0.532 0.9580 0.9877 0.2481 0.4375
40 0.3465 0.9825
0.2368 0.9848
1.5083 0.9740
5.9327 0.9680
10.049 0.9603

Table 2 Selected linear fitting results of kinetic mechanism functions for form IV.
Mechanism code Tm (Tn)/K
535.25 (538.35) 538.35 (543.15) 543.15 (548.75) 548.75 (553.65) 538.35 (548.75)
b r b r b r b r b R
1
0.0170 0.9906
0.0366 0.9911
0.0641 0.9974
0.0726 0.9952
0.1008 0.9916
6
0.0038 0.9828
0.0103 0.9817
0.0076 0.9765
0.0687 0.9694
0.0379 0.9778
11 0.0208 0.9960 0.0286 0.9994 0.0201 0.9971
0.0143 0.9870 0.0499 0.9985
15 0.0080 0.9992
0.0096 0.9972
0.0529 0.9922
0.1745 0.9808
0.0625 0.9941
16
0.0147 0.9965
0.0422 0.9937
0.1225 0.9878
0.3395 0.9670
0.1646 0.9899
20
0.0370 0.9571
0.1889 0.9561
1.3331 0.9540
12.685 0.9520
1.5220 0.9543
25 0.0029 0.9996 0.0055 0.9997 0.0088 0.9994 0.0163 0.9971 0.0143 0.9996
26
0.0115 0.9975
0.0222 0.9977
0.0336 0.9983
0.0297 0.9972
0.0558 0.9981
35
0.0485 0.9888
0.1539 0.9830
0.5735 0.9725
0.7274 0.9752
2.9229 0.9591
40
0.2229 0.9811
0.8077 0.9738
4.1048 0.9626
43.528 0.9532
4.9125 0.9532

Substituting of Ea and A for felodipine form I and IV into

Table 3 ln[b/(Tn
Tm)] versus 1/Tn linear regression equation
Arrhenius equation k = Aexp(
Ea/RT), the pk value is 8.17
for form I and IV.
and 10.62, respectively. Accordingly, shelf life of form I is
an–am form I form IV 3 years and form IV is 4–5 years, coincide with form IV has
0.4–0.2 y =
10639x + 18.132 y =
12155x + 22.043 higher solid state thermal stability.
r = 0.9860 r = 0.9999
0.5–0.4 y =
10331x + 18.199 y =
12198x + 22.799 3.5. Transition temperature and thermodynamic parameters
r = 0.9981 r = 0.9965
0.6–0.3 y =
10722x + 17.853 y =
11955x + 21.254
The solubilities of two forms in 20% ethanol aqueous at 25,
r = 0.9887 r = 0.9993
0.7–0.5 y =
10637x + 18.052 y =
11952x + 21.616
31, 37, 42, 52 °C are listed in Table 5. Usually, low melting
r = 0.9885 r = 0.9985 point correlating with good solubility as predicted by ideal sol-
0.8–0.2 y =
10612x + 17.014 y =
11968x + 20.608 ubility theory, in this study, form IV has a higher melting, but
r = 0.9920 r = 0.9992 its solubility is also higher, which can be explained from crystal
structures [9]. In both forms, the N–H  O=COC2H5 hydro-
gen bonds with comparable energies (compared from hydro-
gen bonding parameters, such as bond lengths and bond
angles) are observed in the lattice. Besides that, in the
felodipine form I and IV conversed into two amorphous state supramolecular arrays of form I, N
H  O=COCH3 interac-
before decomposition, it can be deduced from this, the distinc- tions as well as aromatic stacking are found. Thus, the inter-
tions of thermal decomposition mechanism and activation molecular forces in form I is more abundant than that in
energy of form I and IV may result from the differences in form IV, means that the dissolution of form I needs to destroy
the two amorphous states. more force and requires more energy, leading to the solubility
Thermal properties of drug polymorphs: A case study with felodipine form I and form IV 481

Table 4 Activation energy Ea, pre-exponential factor A, and linear regression for form I and IV (n = 3).
an–am Ea,I/kJ/mol lnAI Ea,IV/kJ/mol lnAIV
0.4–0.2 88.45 16.64 101.1 20.43
0.5–0.4 85.89 16.11 101.4 20.49
0.6–0.3 89.14 16.89 99.39 20.05
0.7–0.5 88.44 16.89 99.37 20.01
0.8–0.2 88.23 16.90 99.50 20.10
Average 88.03 ± 1.24 16.69 ± 0.34 100.2 ± 1.01 20.22 ± 0.23
Ozawa method 91.31 ± 0.5918 17.94 ± 0.19 111.4 ± 3.82 22.46 ± 0.81
Kissinger method 92.64 ± 1.0544 17.67 ± 0.28 112.07 ± 2.08 22.98 ± 0.82

Table 5 Solubility of form I and form IV in 20% ethanol

aqueous at different temperatures (lg/ml) (n = 3).
T/K form I form IV
298.15 15.90 ± 0.03 17.52 ± 0.03
301.15 20.67 ± 0.07 22.76 ± 0.05
304.15 26.04 ± 0.13 28.29 ± 0.05
310.15 37.61 ± 0.10 39.95 ± 0.13
315.15 49.20 ± 0.06 50.27 ± 0.11
325.15 76.63 ± 0.16 75.87 ± 0.10

of form IV was better than the form I, which confirmed that

the microstructure and theoretical calculations are consistent
[45].
The curves with lnc versus 1/T were shown in Fig. 8. The
values of 4HI and 4HIV (see Table 6) suggesting form I has
larger heat of dissolution and smaller solubility, and form IV
possesses smaller heat of dissolution and larger solubility.
The transition temperature (Tt) between form I and IV is
322.23 K, this means when the drug-saturated solution is
cooled, form I crystallize below Tt, and form IV be crystalliza-
tion above Tt [35]. As the result, 4GI,IV decreases with the
increase of temperature. In terms of energy, the main factor
affecting 4GI,IV is TDSI,IV, that is, the entropy is the main
driving force of two polymorphism conversion. For instance,
at 315.15 K, the temperature is lower than Tt (322.23 K), the
experimental value of 4GI,IV (0.08 kJmol
1) is greater than
zero but less than zero (
0.03 kJmol
1) at 325.15 K, a temper-
ature is higher than Tt, this means the transformation reaction
is spontaneous at the higher temperature, that is form I can
Fig. 8 The lnc ~ 1/T curves of form I and IV in 20% ethanol
solution.
spontaneously conversed into form IV at 325.15 K. This result
is consistent with the transformation direction inferred from
Tt. Commonly, for the absorption of drug in human body,
when the difference of free energy between polymorphs is
large, the absorption of the drug would be affected by the crys-
tal forms [12]. Herein, the value of 4GI,IV between felodipine
polymorphs I and IV may be considered small, so the absorp-
tion of the two forms should be no significant difference. This
connection of the thermodynamic properties of drug poly-
morphs and their bioavailabilities in humans provides an
insight into the relationship between drug activity and crystal
form.

Table 6 Thermodynamic parameters of form I and IV in 20% ethanol solution.

T (K) 4HI (kJmol
1) 4HIV (kJmol
1) 4HI,IV (kJmol
1) Tt (K) 4SI,IV (Jmol
1K
1) 4GI,IV (kJmol
1)
298.15 46.54 43.06 3.48 322.23 10.80 0.26
301.15 0.23
304.15 0.20
310.15 0.13
315.15 0.08
325.15
0.03
482
4. Conclusion
In conclusion, the solid thermal decomposition kinetics and
solution thermodynamics between felodipine form I and IV
have been studied in this work. Due to different thermal
decomposition characteristics of felodipine polymorphism,
decomposition mechanisms of felodipine form I and IV are dif-
ferent in terms of Popescu analysis method. Form I is obeyed
nucleation and growth of Avremi–Erofeev equation, integral
form are G(a) = [
ln(1
a)]3/4. Form IV follows Mample
Powel law, G(a) = a. The different thermal decomposition
mechanisms of form I and IV can be explained by the distinc-
tion of amorphous intermediate states conversed before the
crystal collapse. In solution, form I polymorphism is thermo-
dynamically stable with lower solubility at room temperature.
The Gibbs free energy differences obtained from the solubility
data of two polymorphs confirm that the two forms are enan-
tiotropic with the transition temperature of 322.23 K and the
main driving force of conversion is entropy. This work will
provide a deep insight into the thermal decomposition and
thermodynamically stable of other drug polymorphs.
Conflict of interest
The authors report no declarations of interest.
Acknowledgements
This work was supported by the Natural Science Foundation
of Hebei Province of China (Grant Nos H2016206096 and
H2017206214) and sponsored by Education Department of
Hebei Province of China through innovative hundred talents
support program (SLRC2017047).
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