Accepted Manuscript

Title: Heat capacity and enthalpy of indapamide

Authors: M. Skotnicki, A. Drogon,´ J.J Calvin, P.F Rosen,

B.F Woodfield, M Pyda

PII: S0040-6031(18)30140-0
DOI: https://doi.org/10.1016/j.tca.2019.01.032
Reference: TCA 78216

To appear in: Thermochimica Acta

Received date: 30 April 2018

Revised date: 25 January 2019
Accepted date: 28 January 2019

Please cite this article as: Skotnicki M, Drogon´ A, Calvin JJ, Rosen PF, Woodfield
BF, Pyda M, Heat capacity and enthalpy of indapamide, Thermochimica Acta (2019),
https://doi.org/10.1016/j.tca.2019.01.032

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 Heat capacity and enthalpy of indapamide

Skotnicki M.1*, Drogoń A.2, Calvin J.J.3, Rosen P.F.3, Woodfield B.F.3, Pyda M.2*

1
Department of Pharmaceutical Technology, Poznań University of Medical Sciences, 60-780 Poznań,
Poland
2
Department of Chemistry, Rzeszów University of Technology, 35-959 Rzeszów, Poland.
3
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA.

*
Corresponding authors:

Marcin Skotnicki, Department of Pharmaceutical Technology, Poznań University of Medical Sciences,

ul. Grunwaldzka 6, 60-780 Poznań, Poland
Tel.: 0048 61 854 66 55, E-mail address:
marcskot@ump.edu.pl and
Marek Pyda, Department of Chemistry, Rzeszów University of Technology, al. Powstańców
Warszawy 12 35-959 Rzeszów, Poland
Tel.: 0048 17 86 51 995, E-mail address: mpyda@utk.edu

Graphical abstract

600
Indapamide
500 h(liquid)
Enthalpy / J *g -1

hDSC (exp-am on cooling) h

fus
400

hDSC (exp-aged)
300 Tm
1,2
hDSC (exp-cr)
J g - * K-1

1,0 PPMS 200

Ta
1

c (exp)
Heat

p 0,10
PPMS
0,8
*J/Capacit
Hea Capacit / *

cp (fit)
0,08 100 h(crystal)
0,04
y

0,6 0,06

0
y

0,4
g -* K -

0,02 200 250 300 350 400 450 500

1

0,2
t

0 5 1015
1

0,00
20 Temperature / K
Temperature / K
0,0
0 50 100 150 200 250 300
Temperature / K

1
Highlights

  The heat capacities (cp’s) of indapamide (IND) are reported from 1.84 to 523.15 K
  The cp’s of IND were fitted to Debye and Einstein functions (T>54.15 K)
 Absolute cp and equilibrium enthalpy of solid and liquid IND phases are presented

Abstract

The heat capacities and total enthalpy of anhydrous indapamide (IND, CAS no.: 26807-65-8) are reported
from temperature 1.84 to 523.15 K measured byMANUSCRIPTaQuantumDesignPhysicalPropertyMeasurement

System® (PPMS) and differential scanning calorimetry (DSC). The low-temperature experimental heat
capacities of crystalline IND from 1.84 to 302.65 K were measured by PPMS and fit to a theoretical model in
the low temperature range (T < 7.68 K), orthogonal polynomials in the middle temperature range
(7.68 < T < 54.15 K), and a combination of Debye and Einstein functions in the high temperature range
(T > 54.15 K). The calculated heat capacities were extended to a higher temperature to be used as a reference
line of solid heat capacity, cp(solid). The experimental heat capacity of liquid, cp(liquid) for amorphous
indapamide above the glass transition (Tg(midpoint on cooling) = 369.7 ±0.6 K) was approximated by linear
regression and was expressed as cp(liquid) = (0.954 + 0.0023T) J·K–1·g–1. The solid and liquid heat capacities
of IND were applied as reference lines for advanced thermal analysis of the experimental, apparent heat
capacity data measured by DSC. The change in heat capacity (cp) of 0.45 J·K–1·g–1 at g for fully amorphous

IND and heat of fusion fush = 77.5 ±0.7 J·g–1 at melting temperature (Tm = 439.7 ±0.4 K) of 100% crystalline
anhydrous IND were determined. Knowing equilibrium parameters of phase transitions of
amorphous and crystalline forms of IND and heat capacities of solid and liquid IND, total enthalpies for
bothACCEPTEDphaseswerecalculated.ataforunagedand physically aged at 358.15 K for 32 hours amorphous IND
were presented in the context of absolute heat capacity and integral equilibrium enthalpy of solid and liquid
IND phases.

Keywords

indapamide, crystalline and amorphous state, low-temperature heat capacity, equilibrium parameters of
transition phases, thermodynamic function of enthalpy, calorimetry

2
Introduction

Indapamide (IND, Table 1) is an active pharmaceutical ingredient (API) used in the management of
hypertension or heart failure. It is marketed in its crystalline form as a hemihydrate.
APIs may exist in various solid forms and can be classified into two major categories: crystalline
or amorphous [1]. In the crystalline state, the three-dimensional long-range order of the molecular
network is present. Amorphous solids possess no long-range order, however, the short-range order might
exist [2]. The solid state of APIs may have a significant impact on the processability of the drug and the
pharmacological effect of the formulated drug [3-5]. For example, the dissolution rate is usually higher
for amorphous materials in comparison to their crystalline counterparts and is usually linked with
increased bioavailability of the drug [6-9].
The amorphous (glassy) state is a high-energy state, hence amorphous APIs are usually less physically
stable than their crystalline counterparts due to the tendency to reorganize into more ordered form, by process
of devitrification [10]. Therefore, the stability of disordered, metastable state is a major issue hindering its
applicability as pharmaceutical products. For instance, the blockbuster, lipid-regulating drug, atorvastatin, was
initially formulated as an amorphous salt, however, it was observed during the phase
III clinical trials that drug had crystallized and as a result, physicochemical properties had changed
causing the delay in launching drug onto the market [11]. Also, it is known that amorphous materials can
exhibit different physicochemical properties depending on previous thermal history and storage time
(physical ageing, i.e., structural relaxation towards thermodynamic equilibrium) [2, 12-14] which is
indeed an important issue from a pharmaceutical industry point of view [15, 16].
The bioavailability and stability of API can also be a concern in relations to the crystalline solids.
Crystal polymorphism, defined as the ability of a substance to exist as two or more crystalline phases that have
different arrangements and/or conformations of the molecule in the crystal lattice [17], can affect the
bioavailability and stability of the final dosage form [3-5]. For example, Bristol-Myers Squibb in 2010–11

recalled over 60 million tablets of Avalide®, containing two hypotensive APIs (irbesartan and
hydrochlorothiazide) due to the appearance of a less-soluble irbesartan polymorph [5]. Crystalline solid may
incorporate solvent into the crystal lattice of the parent substance (termed: solvates or pseudopolymorphs). If
the solvate is water, what is usually the case for pharmaceuticals, the material is termed a hydrate. The
physicochemical properties of solvates may vary significantly from anhydrous material [1], hence it is essential
to detect and characterize these systems. Thermodynamic factors such as configurational entropy, enthalpy and
Gibbs free energy play an important role in the stability of the amorphous, polymorphic and
pseudopolymorphic systems [18]. The fundamental thermodynamic parameters are a key to understand the
stability and the storage conditions of the solid material. Thus, it is of paramount importance to know basic
thermodynamic functions for API in order to predict its stability in a particular storage condition. Knowing the
heat capacity (Cp) in the wide range of temperature, it is possible to calculate thermodynamic functions such as
enthalpy (H), entropy (S), and Gibbs free energy (G) [19-27]. This method has been used by us and others for
thermodynamic function determination of pharmaceuticals [19-24]. Furthermore, knowing the reference states
Cp(liquid) and Cp(solid), it is possible to apply
3
quantitative advanced thermal analysis to characterize the systems. The reference states Cp’s at the solid
state and liquid state may be applied as the reference lines for the advanced thermal analysis of the
experimental, apparent heat capacity data. The solid Cp at reference states can be estimated based on the
calorimetric measurements of the low-temperature Cp using a Quantum Design Physical Property
Measurement System® (PPMS) and Advanced Thermal Analysis System (ATHAS) [25-27]. These
experimental low-temperature Cp’s at the solid state can be linked to the vibrational molecular motion. At
higher temperatures, above Tg, the liquid Cp can be derived from the molecular large-amplitude motions
(anharmonic and conformational motions) [26-28]. Another option to estimate the reference states Cp at

liquid state can be done by fitting of experimental MANUSCRIPTdatatothelineartemperaturedependenceoralsofrom

the approximation of contributing Cp of similar atoms groups of molecules through a simple ddition
Scheme [25-27]. The ATHAS approach allows for more advanced analysis of the phase transitions such
as glass transition, melting or crystallisation, the accurate determination of their thermal parameters and
also a detailed investigation of the physical ageing process.
The differences in the solid forms often lead to differences in thermodynamic parameters and
physicochemical properties (e. g.: dissolution rate, stability or mechanical properties) [3-5]. The
thermodynamic functions are fundamental for the interpretation of the structure-property-processing
relation in the pharmaceutical materials. Thus, the thermodynamic characterisation of API is crucial for
manufacturing the final dosage form to achieve the intended pharmacological goal. Some thermodynamic
properties of crystalline (polymorphs and pseudopolymorphs) and amorphous indapamide were published
[29-33], however, to our best knowledge, there is no report on heat capacity measurement on such wide
range of temperature for indapamide.
In this work the thermodynamic properties of anhydrous amorphous and crystalline indapamide,
including glass transition, melting point, the enthalpy of fusion and heat capacities, were determined by
differential scanning calorimetry (DSC) and Physical Property Measurement System® in the temperature
range from 1.84 to 523.15 K. Also, the example of advanced thermal analysis for amorphous unaged,
physically aged at 358.15 K for 32 hours (0% relative humidity, RH), and crystalline IND was presented
in the context of absolute heat capacity and integral equilibrium enthalpy of solid and liquid IND phases.
1. Materials and Methods

1.1. Material

Indapamide (IND; M = 365.835 g·mol−1; CAS no.: 26807-65-8; Table 1) was obtained from Polpharma,
Starogard Gdanski, Poland. It was supplied in the form of hemihydrate as a white crystalline powder of
pharmaceutical grade (purity ≥99%). Degradation of investigated material starts around 533 K as measured by
TGA (Figure S1, Supplementary Material). The unhydrated crystalline sample was obtained immediately prior
to experimental measurements in DSC pan in the instrument by heating sample to 424.15 K holding for 3 min,
followed by cooling to the room temperature with rate of 10 K·min−1 In the sample used for PPMS
measurements the water was removed by putting the sample to the oven and holding for 15 min at 424.15 K.
The amorphous form of IND was prepared immediately prior to experimental

4
measurements in DSC pan in the instrument, by heating sample to 463.15 K, holding for 3 min, then
cooled at 10 K·min–1 rate to the room temperature.
Table 1. Specification of chemical sample used.

Initial mass Purification

Chemical name Chemical structure Source
fraction purity method

4-chloro-N-(2-methyl- Polpharma,
2,3-dihydro-1H-indol- Starogard None, used
≥99%
1-yl)-3- Gdanski, as received
sulfamoylbenzamide Poland
1.2. The low-temperature heat capacity measurementsMANUSCRIPTbyPhysicalPropertyMeasurementSystem ® The

low-temperature heat capacity measurements were carried out using a relaxation method of Quantum

Design PPMS in zero magnetic field at constant pressure (p = 1.2 mPa) over the temperature range (1.84 to
302.65) K. Data points were acquired with logarithmic spacing below T = 100 K, and with around 10 K
temperature intervals from T = (100 to 302.65) K. Three data points were taken at each temperature and
averaged to give more accurate results. The sample was dispersed in a copper cup with a small coil of copper
foil to increase thermal conductivity. The pellet was loaded onto the sample platform with a small amount of
Apiezon N grease to provide thermal contact, and the heat capacity was measured. The contribution to the heat
capacity from the copper was subtracted from the total measured heat capacity to yield the heat capacity of the
compound. The estimated standard uncertainties in the temperature T and pressure p are u(T) = 0.004 K and
u(p) = 0.10 mPa. The expanded uncertainties at approximately 95 percent
(exp)PPMS are U( (exp)PPMS) = 0.02∙C(exp)PPMS(T/K < 10) andU( C

confidenceACCEPTEDlimitsinthevaluesofp p p p (exp)PPMS) = 0.01∙ p(exp)PPMS (10 < T/K < 300)

[34]. Further details of sample mounting and the heat
capacity experimental procedures can be found elsewhere [35]. Other examples of the Quantum Design
PPMS application for different materials can be found in the literature [36-38].

1.3. The heat capacity measurements by DSC

DSC curves were obtained using a heat-flux DSC, Discovery Q2500 (TA Instruments – Waters LLC; New
Castle, USA) under a dry nitrogen gas flow of 50 mL·min–1. Sample powders (3–10 mg) were crimped in a

Tzero hermetic aluminium pan with a hole. The crystalline samples were first preheated at 10 K·min–1 rate
from room temperature to 424.15 K and held for 3 minutes to remove water followed by cooling to the room
temperature with the same rate. Then, the pan was weighted again to determine the mass of unhydrated IND.
Next, the sample was heated from 233 to 523.15 K at 10 K·min–1 rate. The amorphous samples were heated

from 233 to 463.15. K and cooled at 10 K·min–1 rate to room temperature. This heating-cooling cycle was
repeated. The amorphous samples for isothermal physical aging experiments were heated first above Tg and Tm
to 463.15 K and held for 3 minutes to eliminate the effect of prior thermal history and then cooled at 10
K·min–1 to the aging temperature (358.15 K) The samples were maintained at the aging temperature for 32

hours, and after aging, samples were cooled at 10 K min–1 to the room
5
temperature and subsequently heated at 10 K·min–1 to 463.15. The equipment was calibrated with indium (m.

p. = 429.80 K, hfus = 28.45 J·g–1), and at least two tests were run on each sample. Two decimals in temperature
values result from the change of °C into K. In order to obtain accurate results of heat capacity, data were
calibrated using the heat capacity of sapphire. Additionally, the DSC experimental data for the crystalline
sample were also calibrated to the Debye-Einstein fit (solid reference line). The phase transitions parameters of
crystal and amorphous IND were evaluated from raw data of heat-flow rates. Melting and enthalpy recovery
events are quoted as an onset temperature. The heat of fusion for crystalline IND was integrated with
sigmoidal baseline type. Glass transition temperatures are quoted as midpoints, i.e. the

2. Results and Discussion

midpoint of the glass transition temperature rangeMANUSCRIPTboundedbythetangentstothetwoflatregionsofthe
heat flow curve. The experimental apparent heat capacities were obtained by DSC from the evaluation of
measured heat-flow rates at the run, after preheating to dehydrate with a heating rate of 10 K·min–1 for
crystalline IND. For amorphous IND data were collected from the third heating run after controlled
cooling at 10 K·min–1. All values were determined using TRIOS v. 4.3.0 (TA Instruments – Waters LLC;
New Castle, USA) software. Errors are quoted as a standard uncertainty type .

Figure 1 shows the standard DSC traces of indapamide with a 10 K·min–1 heating and cooling rate. The 1st
heating curve (A) of, as-received hemihydrate crystalline material heated from 250 to 424.15 K, shows one
endothermic event. The small broad peak with an onset at 320.85 ±2.3 K ( h = 43.2 ±1.2 J·g–1) is related to
fus

the loss of water. Next, the material was cooled down to 233.15 K, and Figure 1 shows a result of the second
heating as curve (B) of the dehydrated material. The DSC curve (B) shows one sharp endothermic
peak. This event is related to melting (Tmonset = 439.7 ±0.4 K and h = 77.5 ±0.7 J·g–1) and confirms that
fus

indapamideACCEPTEDwasafullycrystallinematerial.This anhydrous form is a different phase than the anhydrous

form-I reported by Ghugare et al. [30] with the melting 459.99 K and a heat of fusion 156.3 J·g –1. Next,
during the cooling run (curve C, Figure 1) to 233.15 K from the molten state, one event is observed, a glass
transition with Tg at 369.7 ±0.6 K. In this run the physical ageing is not present. One event is also observed on
the third heating run (curve D, Figure 1), a glass transition at 375.4 ±0.4 K (determined by midpoint)
overlapped with some enthalpy recovery. A similar value of Tg was obtained from broadband dielectric
spectroscopy (BDS) and DSC by Wojnarowska et al. [29] (TgBDS = 374 K and TgDSC = 377 K), Edueng et al.

(TgDSC = 375.15 K) [32] and slightly higher than that, reported by Serajuddin et al. [31] (TgDSC = 371 K) with

a change of heat capacity as determined from the DSC heat-flow data (Δcp) of 0.48 ±0.01 J·K–1 g–1 indicating
amorphisation of crystalline indapamide after melting and cooling the sample. Our result of the
 cp at g for fully amorphous sample determined from the reference states cp’s at the solid state and liquid state
was calculated to be 0.45 J·K–1 g–1. The cp value is in good agreement with that reported by Knapik et al.

(0.49 J·K–1 g–1) [33]. The glass transition is a kinetic transition and depends on cooling rate. Tg is accurately
measured on cooling from the equilibrium state, leading to the mentioned Tg determined by midpoint at 369.7
K, which is correct in this case due to the absence of enthalpy relaxation during cooling. However, in the case
of subsequent isothermal storage below Tg (at 358.15 K) physical aging occurs

6
showing as enthalpy relaxation on the DSC curve as presented later on. On heating of such an aged
amorphous sample, considerable enthalpy recovery takes place, giving arise to a quite strong recovery
peak during heating. In such case the determination of Tg by midpoint, leading to approximately 377 K,
should be rejected and instead the fictive temperature (Tf) or Tg-recovery has to be calculated. The fictive
temperature defines the structure of glass and is measured on heating for the aged amorphous sample. The
fictive temperature is the temperature at which the property of interest, e.g., specific volume or enthalpy,
when extrapolated along the glass line intersects the equilibrium liquid line [28, 39, 40]. Thus, there are
differences between the glass transition recovery temperatures (fictive temperature) for aged (non- and
iso-thermally) and the glass transition of unaged (from cooling) samples. In the present case, fictive
temperature for sample aged at 358.15 K for 32 hour is 358.7 K.

exo up
A
-0.5 water evaporation

-1.0
B melting
/W g-1

-1.5
flo

-2.0
w Heat

-2.5 glass transition on cooling

C

-3.0
D glass transition on heating

-3.5
ACCEPTED250300 350 400 450 500

Temperature / K

st
Figure 1. The experimental, raw DSC data of the heat-flow rate versus temperature for indapamide. A – 1 heating run to 424.15
K for hemihydrate crystalline material (carried out in order to evaporate water), B – a heating run for the anhydrous
crystalline material, – a cooling run from the melt, D – a heating run of amorphous material.

Figure 2 presents dependence of the experimental, low-temperature heat capacity on temperature using the
relaxation method of Physical Property Measurements System® and their fit to the equations (1), (2) and
(3) (solid lines). The Debye-Einstein fit was used to describe heat capacities in the range between 54.15
and 302.64 K as recommended by the authors in Ref. [41]. The measurements were performed in the
temperature range from 1.84 to 302.65 K. Additionally, magnified data are presented from T = (1.84 to
20) K in the insert of Figure 2. Also, the results of the experimental low-temperature heat capacity from
PPMS measurements are listed in Table 2. No phase transition in the temperature range from 1.84 to
302.65 K was observed, and the heat capacity was continually increasing (Figure 2).

7
 1,2

Indapamide
1,0
PMMS
c (exp)
p

-* 1K* -1
cp PMMS (fit)

g
0,8 0,10

/J
0,08
Capa

/CapacityH
city

0,6

eat
0,06
Hea

0,4

*J
t

0,04

g-
1
K
-*
1
MANUSCRIPT
0,02
0,2
0,00
0 5 10 15 20
Temperature / K
0,0
0 50 100 150 200 250 300
Temperature / K

Figure 2. The experimental, low-temperature heat capacity of indapamide (dots) versus temperature measured with a Quantum
Design Physical Property Measurements System from 1.84 to 302.65 K. The insert shows data from T = 1.84 to 20 K.
Solid lines represent results from fittings to the equations (1), (2) and (3).
PPMS
Table 2. The experimental heat capacities cp (exp) for indapamide measured by PPMS from = (1.84 to 302.65) K at constant
pressure (p = 1.2 mPa).

T/K cp / J·K–1·g–1 T/K cp / J·K–1·g–1 T/K cp / J·K–1·g–1

1.839 1.5254 e-4 6.894 9.0945 e-3 45.415 0.2140
1.903 1.6789 e-4 7.201 0.0102 49.631 0.2323
1.985 1.9377 e-4 7.521 0.0113 54.236 0.2523
2.068 2.2358 e-4 7.857 0.0126 59.270 0.2736
2.155 2.5881 e-4 8.208 0.0141 64.773 0.2958
2.246 2.9284 e-4 8.574 0.0156 70.778 0.3186
2.344 3.2769 e-4 8.956 0.0174 77.353 0.3442
2.443 3.8711 e-4 9.354 0.0191 84.496 0.3742
2.547 4.3268 e-4 9.769 0.0211 92.365 0.4049
2.656 4.9424 e-4 10.242 0.0233 100.930 0.4320
2.770 5.7384 e-4 10.696 0.0256 111.030 0.4661
2.891 6.5562 e-4 11.171 0.0279 121.080 0.5039
3.017 7.4378 e-4 11.669 0.0305 131.200 0.5379
3.149 8.6350 e-4 12.188 0.0333 141.280 0.5711
3.291 9.8810 e-4 12.727 0.0363 151.330 0.6074
3.436 1.1526 e-3 13.289 0.0394 161.440 0.6414
3.587 1.3066 e-3 13.876 0.0427 171.530 0.6747
3.744 1.5404 e-3 14.491 0.0462 181.610 0.7072
3.911 1.7730 e-3 15.133 0.0499 191.680 0.7406
4.086 2.0311 e-3 15.635 0.0529 201.770 0.7740
4.269 2.2896 e-3 17.089 0.0614 211.850 0.8062
4.459 2.6050 e-3 18.681 0.0708 221.950 0.8382
4.656 2.9727 e-3 20.406 0.0813 232.030 0.8709
4.862 3.4037 e-3 22.315 0.0921 242.100 0.9036
5.079 3.8504 e-3 24.389 0.1041 252.190 0.9377
5.306 4.3859 e-3 26.647 0.1169 262.280 0.9708
5.543 5.0159 e-3 29.127 0.1310 272.380 1.0038
5.790 5.6277 e-3 31.832 0.1458 282.460 1.0370
6.050 6.4037 e-3 34.789 0.1614 292.530 1.0653
6.318 7.1918 e-3 38.024 0.1780 302.640 1.0973
6.599 8.1269 e-3 41.555 0.1955 302.650 1.1110
a
The estimated standard uncertainties in the temperature T and pressure p are u(T) = 0.004 K and u(p) = 0.10 mPa. The expanded uncertainties at
approximately 95 percent confidence limits in the values of Cp(exp)PPMS are U(Cp(exp)PPMS) = 0.02∙ Cp(exp)PPMS (T/K < 10) and U(Cp(exp)PPMS) =
0.01∙ Cp(exp)PPMS (10 < T/K < 300).
8
The experimental heat capacity from T = 1.84 to 302.65 K was divided into three regions for fitting: a low
temperature region (1.84–7.68 K), a medium temperature region (7.68–54.15 K), and a high temperature
region (54.15–302.64 K).
The low temperature region was fit with the function:
= ∑
(1)
=3,5,7,…

where all terms represent lattice contributions to heat capacity. There is no linear term in the fit, which is
unsurprising because indapamide is not be expected to have electronic or magnetic properties.
MANUSCRIPT
The second temperature region was fit using an orthogonal polynomial:
= ∑

(2)
=0,1,2…7

This fit has no physical significance. It is simply used to bridge the gap between the low and high
temperature regions.
The third temperature region was fit with the function:
Θ Θ
ℎ ℎ = · ( )+ · ( )+ · 2
(3)

where (Θ / ) and (Θ / ) are Debye and Einstein functions, respectively, and m, n, Θ , and Θ are adjustable parameters. Because these
functions give constant volume heat capacity, the square term is added to convert to constant pressure heat capacity. The parameters to
these fits are given in Table 3.

Table 3. Parameters for low temperatures T (< 7.68 K), mid (7.68 K < < 54.15 K), and high T (T > 54.15 K) fits of heat
–1 –1 PP S
capacity data (in J∙K ∙mol ) for indapamide, Cp (fit). Coefficients are obtained from a fit of the experimental heat
capacity with equation (1): B3, B5, B7, B9, (2):A 0, A 1, A2, 3, 4, 5, 6, 7 and (3) ΘD, ΘE, A.
M
D

w
C
C
A

E
P

L
T

T
F
d

o
s

s
i

i
t

i
t

Parameter Value
–4 –1 –3
B3 / J∙K ·mol 8.662∙10
–6 –1 –4
B5 / J∙K · mol 1.711∙10
–8 –1
B7 / J∙K · mol –3.909∙10–6
–10 –1 –8
B9 / J∙K · mol 2.201∙10
%RMS 1.81
Range / K 1.84-7.68
–1 –1
A0 / J∙K · mol 1.731
–2 –1
A1 / J∙K · mol –1.173
–3 –1
A2 / J∙K · mol 0.2664
–4 –1
A3 / J∙K · mol –1.044∙10–2
–5 –1 –4
A4 / J∙K · mol 2.076∙10
–6 –1
A5 / J∙K · mol –1.858∙10–6
–7 –1 –9
A6 / J∙K · mol 1.169∙10
–8 –1 –11
A7 / J∙K · mol 5.899∙10
%RMS 0.200
Range / K 7.68-54.15
m / mol
ΘD / K
High T Fits

n / mol 5.927
ΘE / K 187.639
–3 –
A/ J∙K · mol 5.467
574.641
1
%RMS –
1.704∙10 3
0.517
9
 Range / K 54.15-302.64

The calculated heat capacity of indapamide in the solid state from 1.84 to 302.65 K expressed by equations

(1), (2) and (3) is next called the solid heat capacity, cp(solid) ≡ cpPPMS(fit). The calculated heat capacity,
cp(solid), was extended to a high temperature up to 500 K using equations (1) and (2) for the range of
temperatures from 0 to 50 K and using Debye and Einstein functions (3) for higher temperature and was
applied as a reference line of solid heat capacity for thermal analysis of experimental crystalline and
amorphous indapamide (in Figure 3 this is described as cp(solid)). The recommended reference lines data
for heat capacities are presented in the Table 4.
with a standard deviation of ±0.5%. The equationMANUSCRIPT(4)wasusedforfurtherthermalanalysis.InFigure3a and b the calculated heat capacities of liquid, cp(liquid) and solid cp(solid) of indapamide are used as a

Figure 3a and b show sets of heat capacities of crystalline, cpDSC(exp-cr) and amorphous, cpDSC(exp-am
on heating) indapamide obtained for data on 2nd (curve B) and 3rd (curve D) heating runs as presented in
Figure 1 together with the low-temperature cpPPMS(exp) for crystalline IND. Also, Figure 3a and b
display the comparison of the experimental data in the solid state below glass transition temperature, Tg
=375.4 K of cpDSC(exp-am on heating) and below the melting transition temperature, Tm = 439.7 K of
cpDSC(exp-cr) with calculated cp(solid).

The measured heat capacities for the liquid state above g for cpDSC(exp-am on heating) of amorphous
sample were fit to a linear function, Eq. (4):

cp(liquid) = (0.954 + 0.0023T) J·K–1·g–1 (4)

reference lines between 0 and 500 K for thermal analysis of experimental data of cpDSC(exp-am on
heating) and cpDSC(exp-cr). It needs to be noted that unaged amorphous sample (exp-am on heating)
(Figure 3b, green line) presents a small enthalpy recovery peak. This indicates that the material had
undergone some physical ageing process during cooling and heating of the sample [39]. The physical
ageing is not present at all during the cooling run of a liquid sample from the melt (Figure 4, green line).
g 1 K-1
*

4
-
*

a 4
Indapamide b Indapamide
J
/
H

C
e
a

a
p
a
c

y
t

t
i

DSC
cp (exp-cr)
/ J g-1 K-1

3
3

DSC
**

cp (exp-am on heating)

2 2
cp(liquid) cp(liquid)

1 1
cp(solid) cp(solid)

PPM S
c (exp) PPM S
p
cp (exp)

0 0
0 100 200 300 400 500 0 100 200 300 400 500

Temperature / K Temperature / K

DSC PPMS DSC

Figure 3. Experimental, apparent heat capacity of a) crystalline, cp (exp-cr), cp (exp) and b) amorphous, cp (exp-am
on heating) indapamide obtained by DSC and PPMS, respectively, in the frame of calculated heat capacity in the solid,

10
 cp(solid) and liquid, cp(liquid) states. The melting endotherm has been truncated to amplify the appearance of the
other curves.

Figure 4 shows a comparison of experimental, apparent heat capacity of amorphous indapamide as measured
by DSC of the unaged sample on cooling, cpDSC(exp-am on cooling) and aged sample on heating, cpDSC(exp-
aged). The amorphous indapamide was aged at 358.15 K for 32 hours at 0% RH. The apparent heat capacity of
this aged amorphous indapamide displays the overlapping of enthalpy recovery peak with a change of heat
capacity at Tg. The heat capacities in Figure 4 were also presented in the frame of reference states of cp(solid)
and cp(liquid). Below and above Tg, the heat capacities of both cpDSC(exp-am on cooling) and cpDSC(exp-aged)
agree with references lines of cp(solid) and cp(liquid). Also, Figure 4 presents the heat capacity of 100%
crystalline IND, cpDSC(exp-cr) which was already shown in Figure 3a and b.

4
Indapamide
cpDSC(exp-cr)

3
/ J g-1 K-1

cpDSC(exp-aged)
**

cpDSC(exp-am on cooling)
2

cp(liquid)

1
cp(solid)

cpPPM S(exp)

0
0 100 200 300 400 500

Temperature / K

DSC DSC
Figure 4. Experimental, apparent heat capacity of crystalline, cp (exp-cr) and amorphous, cp (exp-am on cooling)
PPMS
indapamide obtained by DSC and PPMS, cp (exp), respectively, in the frame of calculated heat capacity in the
solid, cp(solid) and liquid, cp(liquid) states. Also, the heat capacity of aged amorphous indapamide is presented (Ta =
DSC
358.15 K for 32 hours, 0% RH; cp (exp-aged)). The melting endotherm has been truncated to amplify the
appearance of the other curves.

Knowing the heat capacities of solid and liquid as well as the transition parameters, the thermodynamic
function enthalpy, h, can be calculated as a function of temperature, Eq.(5):

ℎ = ℎ0 + ∫ p d (5)

where T is temperature and h0 is constant from the integration.

Figure 5 shows the results of enthalpies (h) as a function of temperature (T) for all heat capacities presented in
Figure 4 in range of temperature from 200 to 500 K. The enthalpy of the solid state is presented in Figure

11
5 as h(crystal), and its calculation was done by the integration of cp(solid) as a function of temperature based
on Debye-Einstein equation (3). The recommended reference lines data for enthalpy from Figure 5 are
presented in the Table 4. At the equilibrium melting temperature, Tm = 439.7 K, enthalpy, h(crystal) is
increased by the heat of fusion 77.5 J·g–1 to reach the equilibrium enthalpy of liquid (melt), h(liquid). The
enthalpy, h(liquid) is the result of the integration of equation (4) and is a quadratic function of temperature.
The enthalpy of fully crystalline IND, hDSC(exp-cr) is a good match with the enthalpy of h(crystal). Also,

Figure 5 presents the enthalpy of unaged amorphous IND with changing of slope in Tg (on cooling) of 369.7 K.
The enthalpy of aged amorphous IND appears below the line of unaged enthalpy. The difference between
unaged and aged enthalpy value at ageing temperature, Ta = 358.15 K, gives the value of enthalpy recovery
and in this case is around 6 J·g–1 and Tf = 358.7 K. Knowing the enthalpies as a function of temperature, as
presented in Figure 5, quantitative thermal analysis of the chosen material can be performed, and it this case, it
will be used for comperhensive physical ageing studies of amorphous indapamide.

600

Indapamide h (liquid)
500

h
f us
400 hD SC(exp-am on cooling)
* -1
g
/J

300 hD SC (exp-aged)

m = 439.7K
Enthalp

MANUSCRIPT
h (amorphous)
hD SC (exp-cr)
y

200
Tf = 358.7 K
100

h (crystal)
T (on cooling) = 369.7 K
g
0
200 250 300 350 400 450 500

Temperature / K

DSC DSC DSC

Figure 5. Experimental, enthalpy of crystalline, h (exp-cr) and amorphous, unaged h (exp-am on cooling), aged, h (exp-aged),
indapamide as measured by DSC in the frame of calculated enthalpy in the solid, h(crystal) = h(solid) and liquid,

12
 DSC
h(liquid) states. Also, the enthalpy of aged amorphous indapamide, h (exp-aged), is presented (Ta = 358.15 K for 32
hours at 0% RH).

Table 4. The recommended reference heat capacity (cp), enthalpy (h) and parameters of transition of crystalline (solid)
and amorphous (liquid) indapamide from temperature, T = (0 to 500) K.

Temperature Heat capacity Enthalpy Heat capacity Enthalpy

/K cp(solid)a / J·g–1K–1 h(solid)b / J·g–1 cp(amorphous)c / J·g–1K–1 h(amorphous)d / J·g–1
0 0.0000 0.0000 0.000 48.9448
1 2.5659e-5 6.4401e-6 2.5659e-5 48.9310
2 2.0476e-4 1.0201e-4 2.0476e-4 48.9221
3 7.3949e-4 5.3385e-4 7.3949e-4 48.9180
4 1.8657e-3 1.7798e-3 1.8657e-3 48.9187
5 3.7039e-3 4.5048e-3 3.7039e-3 48.9242
6 6.2495e-3 9.4250e-3 6.2495e-3 48.9345
7 9.4414e-3 0.0172 9.4414e-3 48.9496
8 0.0132 0.0285 0.013 48.9695
9 0.0175 0.0438 0.018 48.9941
10 0.0221 0.0636 0.022 49.0235
15 0.0491 0.2398 0.049 49.2415
20 0.0786 0.5589 0.079 49.5768
25 0.1078 1.0253 0.108 50.0282
30 0.1357 1.6346 0.136 50.5945
35 0.1624 2.3805 0.162 51.2744
40 0.1879 3.2569 0.188 52.0667
45 0.2119 4.2571 0.212 52.9704
50 0.2342 5.3729 0.234 53.9841
60 0.2785 7.9334 0.279 56.3375
70 0.3191 10.9251 0.319 59.1179
80 0.3561 14.3023 0.356 62.3170
90 0.3918 18.0423 0.392 65.9264
100 0.4272 22.1373 0.427 69.9384
110 0.4627 26.5868 0.463 74.3453
120 0.4982 31.3912 0.498 79.1399
130 0.5335 36.5493 0.534 84.3153
140 0.5685 42.0599 0.569 89.8650
150 0.6030 47.9178 0.603 95.7826
160 0.6371 54.1200 0.637 102.0622
170 0.6706 60.6585 0.671 108.6982
180 0.7037 67.5304 0.704 115.6852
190 0.7363 74.7304 0.736 123.0183
200 0.7687 82.2557 0.769 130.6928
210 0.8007 90.1007 0.801 138.7044
220 0.8327 98.2683 0.833 147.0491
230 0.8646 106.7558 0.865 155.7231
240 0.8965 115.5603 0.897 164.7231
250 0.9285 124.6846 0.929 174.0461
260 0.9607 134.1315 0.961 183.6892
270 0.9932 143.9009 0.993 193.6501
273.15 1.0035 147.0444 1.004 195.9866
280 1.0260 153.9957 1.026 203.9267
290 1.0591 164.4211 1.059 214.5172
298.15 1.0864 173.1628 1.086 223.3798
300 1.0927 175.1801 1.093 225.4202
310 1.1267 186.2793 1.127 236.6345
320 1.16125 197.7204 1.161 248.1593
330 1.1964 209.5093 1.196 259.9942
340 1.2320 221.6521 1.232 272.1390
350 1.2683 234.1549 1.268 284.5939
360 1.3053 247.0243 1.305 297.3593
369.7 Tg 1.3418 259.8643 1.342 309.0749
369.7 Tg 1.3418 259.8643 1.804 309.0749
370 1.3429 260.2667 1.805 309.6163
380 1.3812 273.8891 1.828 327.7813
400 1.4599 302.3011 1.874 364.8013
410 1.5004 317.1052 1.897 383.6563
420 1.5417 332.3177 1.920 402.7413
430 1.5837 347.9464 1.943 422.0563
13
 431 1.5879 349.5325 1.945 424.0004
432 1.5922 351.1228 1.948 425.9469
433 1.59645 352.7173 1.950 427.8957
434 1.6007 354.3161 1.952 429.8467
435 1.6050 355.9192 1.955 431.8001
436 1.6093 357.5266 1.957 433.7557
437 1.6136 359.1382 1.959 435.7137
438 1.6179 360.7542 1.961 437.6739
439 1.6222 362.3744 1.964 439.6365
439.7 Tm 1.6252 363.5116 1.965 441.0116
440 1.6265 363.9990 1.966 441.6013
450 1.6701 380.4833 1.989 461.3763
460 1.7145 397.4075 2.012 481.3813
470 1.7597 414.7798 2.035 501.6163
480 1.8058 432.6087 2.058 522.0813
obtaining more comprehensive characterizationMANUSCRIPTofthematerialwhichisofgreatimportanceto

490 1.8527 450.9026 2.081 542.7763

500 1.9004 469.6705 2.104 563.7013
a
The calculated heat capacity of solid indapamide according to results from fittings to the equation (1) for T= 1.84–7.68 K, to the equation (2) for T= 7.68–
54.15 K, to the equations (3) using Debye and Einstein functions for T= 54.15–500 K. The estimated standard uncertainties in the temperature T and
pressure p are u(T) = 0.004 K and u(p) = 0.10 mPa. The expanded uncertainties at approximately 95 percent confidence limits in the values of
Cp(exp)PPMS are U(Cp(exp)PPMS) = 0.02∙ Cp(exp)PPMS (T/K < 10) and U(Cp(exp)PPMS) = 0.01∙ Cp(exp)PPMS (10 < T/K < 300).
b
The calculated enthalpy of solid indapamide according to the equation (5) where cp is equal cp(solid).
c
The calculated heat capacity of amorphous indapamide are equal cp(solid) until Tg= 369.7 K and above Tg according to the equation (4).
Standard uncertainty of heat capacity measurement obtained by DSC is presented in SUPPORTING INFORMATION in Table S2.
d
The calculated enthalpy of amorphous indapamide according to the equation (5) where cp is cp(amorphous). The amorphous enthalpy,
h(amorphous) ≡ h(liquid) is the result of the integration of equation (4) and is a quadratic function of temperature. At the equilibrium melting
temperature, Tm = 439.7 K, enthalpy of liquid (amorphous) has the value equal of enthalpy, h(solid) increased by the heat of fusion 77.5 J·g–1 (=
441.0116–363.5116).

3. Conclusions and Summary

The heat capacity of anhydrous indapamide form was measured using the PPMS and DSC from = 1.84 to
523.15 K. The enthalpies for liquid and solid states were calculated based on the experimental heat
capacity values.
DSC in conjunction with PPMS enables to obtain complete thermal characteristic of
pharmaceuticals. The knowledge of detailed thermodynamic parameters of anhydrous IND allows

understanding and predicting their macroscopic physicochemical properties such as stability, physical
ageing behaviour or solubility, facilitating the choice of either amorphous or crystalline API. Furthermore,
data published in this study allows performing advanced thermal analysis using the ATHAS scheme.

Acknowledgements

MS gratefully acknowledge Ms Maria Jacewicz from TA Instruments Waters Sp. z o. o. (Warsaw, Poland)
for the provision of Discovery DSC 2500 instrument used in this study. The low-temperature heat capacity
work was supported by the U.S. Department of Energy, Office of Science, Basic Energy Sciences, under
grant number DE-SC0016446.

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