[2012] physicochemical characterization and decomposition kinetics of trandolapril

8/12/2019 [2012] Physicochemical Characterization and Decomposition Kinetics of Trandolapril

http://slidepdf.com/reader/full/2012-physicochemical-characterization-and-decomposition-kinetics-of-trandolapril 1/8

Thermochimica Acta 539 (2012) 92–99

Contents lists available at SciVerse ScienceDirect

Thermochimica Acta

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

Physicochemical characterization and decomposition kinetics of trandolapril

E. Roumelia, A. Tsiapranta b, K. Kachrimanis b, D. Bikiaris c, K. Chrissafis a,∗

a Solid State Physics Section, Physics Dept., Aristotle University of Thessaloniki, Thessaloniki, Greeceb School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, Greecec Laboratoryof Organic Chemical Technology, Dept. of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece

a r t i c l e i n f o

Article history:

Received 24 January 2012

Received in revised form 29 March 2012Accepted 6 April 2012

Available online 15 April 2012

Keywords:

Trandolapril drug

Thermal stability

Decomposition mechanism

Thermal destruction

a b s t r a c t

The purpose of this work was to study the physicochemical properties of trandolapril, to perform a

detailed kinetic study of its decomposition and also to evaluate its thermal stability in order to provide

the essential tools to design a thermal destruction method for expired trandolapril-based drugs. Tran-

dolapril was characterized with FTIR, XRPD and SEM and its thermal behaviour was studied with DSC and

TGA in dry air and nitrogen flows. The decomposition process was also followed by Py-GC–MS, the activa-

tion energy was calculated with isoconversional methods and the reaction model was determined with

model-fitting method. Trandolapril is stable until the onset of its melting (110 ◦C) in both nitrogen and

dry air environments. Thermal degradation of trandolapril can be described by two consecutive mech-

anisms of n-th order with activation energies 97.4 and 180.0 kJ/mol respectively. Trandolapril reaches

zero residual at 510 and 560 ◦C in nitrogen and dry air flow respectively. The detailed analysis of decom-

position mechanism allows the industry to design integrated thermal destruction processes for expired

trandolapril-based drugs. The results of Py-GC–MS agree with the theoretical calculations of thermal

analysis techniques, which highlights that the different techniques used in this work are complementary

and equally important.

© 2012 Elsevier B.V. All rights reserved.

1. Introduction

Trandolapril is the ethyl ester prodrug of a non-

sulfhydryl angiotensin converting enzyme (ACE) inhibitor,

trandolaprilat. Trandolapril is chemically described as

(2S,3aR,7aS)-1-[(S)-N-[(S)-1-carboxy-3-phenylpropyl]alanyl]

hexahydro-2-indolinecarboxylic acid, 1-ethyl ester [1]. It is used

for the treatment of hypertension and its blood pressure lower-

ing effect can be further enhanced by the addition of a diuretic

medication, such as hydrochlorothiazide.

An area that has been gaining more and more attentionrecently

by both the pharmaceutical industry and academic research is drug

disposal and destruction. Concern for the environment, both in

terms of limiting the use of finite resources and the need to man-

age waste disposal, has led to increasing pressure to safely dispose,

destruct or recycle materials at the end of their useful life [2]. Even

though waste management is nowa high priority in every country,

we hardly ever talk about pharmaceutical pollution and therefore,

little, if any, literature is dedicated to studies of pharmaceuticals

∗ Corresponding author at: Solid State Physics Section, Physics Dept., Aristotle

University of Thessaloniki, Thessaloniki, Greece. Tel.: +30 2310 998188;

fax: +30 2310 998188.

E-mail address: [email protected] (K. Chrissafis).

destruction processes. The ultimate challenge nowadays is to pre-

vent medications from being released into the environment.

People nowadays takemore prescription drugs thanever before.

With thousands of pills being washed down the drain or land-

filled, it’s no surprise that pharmaceuticals have been detected in

surface, ground and drinking water in many countries [3]. Cur-

rently there are no concrete guidelines concerning drug disposal

and most people continue to dispose of their medications in the

household garbage or by flushing down the sink or toilet. This is

becoming a global issue and therefore, many countries are evalu-

ating their drug disposal programs [4–6] which also aimto educate

and raise awareness [7]. Because the effects of many pharmaceu-

tical compounds on the environment are not fully understood,

many environmentalists consider sewage-mediated disposal to be

the least desirable means of disposal [8–10]. It is widely believed

that high-temperature incineration is the most environmentally

friendly method for disposal and destruction of unused or expired

pharmaceutical products [11,12]. In certain countries take back

programs have been funded providing the legal framework and

logistics resources to allow people and health care facilities to

return unused or expired drugs so that they can either be reused or

safely incinerated in appropriate facilities [13,14].

In this work trandolapril has been extensively studied with var-

ious techniques and much attention has been paid to its thermal

decomposition, in order to collect essential information needed to

design a possible expired-drug destruction process, which can only

0040-6031/$ – seefrontmatter © 2012 Elsevier B.V. All rights reserved.

http://dx.doi.org/10.1016/j.tca.2012.04.009

http://localhost/var/www/apps/conversion/tmp/scratch_6/dx.doi.org/10.1016/j.tca.2012.04.009


http://www.sciencedirect.com/science/journal/00406031

http://www.elsevier.com/locate/tca

mailto:[email protected]



mailto:[email protected]

http://www.elsevier.com/locate/tca

http://www.sciencedirect.com/science/journal/00406031




E. Roumeli et al./ Thermochimica Acta 539 (2012) 92–99 93

be designed when all the components forming the drug (active,

excipients, etc.) are well studied. It is also important to mention

that no prior thermal stability studies of trandolapril have been

reported in the literature.

2. Materials andmethods

2.1. Materials

Trandolapril crystalline powder with molecular formula

C24H34N2O5 and molecular weight 430.54g/mol was kindly pro-

vided from Chunghwa Chemicals Synthesis and Biotech Co Ltd

(Taipei Hsien, Taiwan).

2.2. Fourier transform infrared spectroscopy (FTIR)

In order to proceed to the optical characterization of tran-

dolapril, FTIR spectroscopy in transmittance mode was used. KBr

pellets with 1w t% of the powdered material were produced.

The spectra were obtained with a Spectrum 1000 PERKIN-ELMER

spectrometer in the spectral range 4000–400cm−1, with 2 cm−1

resolution and 32 scans.

2.3. X-ray powder diffraction (XRPD)

X-ray powder diffraction patterns were recorded by a water-

cooled Rigaku Ultima+ diffractometer using CuKa radiation, a step

size of 0.02◦ and a step time of 3 s, operating at 40kV and 30mA.

2.4. Hot stage polarized optical microscopy (HSPM)

A polarizing optical microscope (Nikon, Optiphot-2 (Tokyo,

Japan)) equipped with a Linkam THMS 600 (Surrey, UK) heating

stage with a TP 91 control unit was used for HSM observations.

2.5. Scanning electron microscopy (SEM)

The morphology of the prepared samples was examined in a

SEM system (JEOL JSM 840A-Oxford ISIS 300microscope). The sam-

ples were carbon coated in order to provide good conductivity of

the electron beam. Operating conditions were: acceleratingvoltage

20kV, probe current 45nA, and counting time 60s.

2.6. Thermogravimetric analysis (TGA)

Thermal stability of trandolapril was evaluated by TGA using

a SETARAM SETSYS TG-DTA 16/18. Samples (6.0±0.2mg) were

placed in alumina crucibles. An empty alumina crucible was usedas reference. The samples were heated from ambient temperature

to 600 ◦C in a 50ml/min flow of nitrogen or dry air, at heating rates

of 5, 10, 15 and 20 ◦C/min. Continuous recordings of sample tem-

perature, sample weight, its first derivative and heat flow were

performed.

2.7. Differential scanning calorimetry (DSC)

Differential scanning calorimetry curves were obtained with

DSC 141, SETARAM instrument. 6.0±0.2mg of each sample was

placed in crimped aluminium crucibles, while an empty one was

used as reference.Samples were heated from ambient temperature

to 180 ◦C ina 50ml/min flowof N2

with a heating rate of 5 ◦C/min.

2.8. Pyrolysis-gas chromatography–mass spectroscopy

(Py-GC–MS)

For Py-GC–MS analysis the drug is “dropped” initially into the

“Double-Shot” Pyrolyzer. The furnace temperature is programmed

from100to 700 ◦C. Thesample was retained at 100 ◦Cfor2min and

heated with a rate 20◦C/min to its decomposition. As the sample is

heated, vapors evolve. Pyrolysis products are flushed through the

split/splitlessinjection portby the carrier gas (nitrogen 50 ml/min).

The sample is split, and a fraction (e.g. 1/50) of the gases passes

through the EGA capillary tube which is kept at 300 ◦C to prevent

condensation. The pyrolyzates are separated using temperature

programmed, capillary column GC and analyzed by the mass spec-

trometer (MS) GCMS-QP 2010. Optimal pyrolysis temperatures can

be determined with the thermogram (EGA chromatogram) as fol-

lows, peak end point of degradation step +50 ◦C.

3. Results and discussion

3.1. XRPD and FTIR characterization

The XRPD pattern of trandolapril is presentedin Fig. 1. Fromthe

study of the XRPD pattern of trandolapril, its high crystallinity can

be seen andthe peaks with higher intensity are observed at 16.95◦,

18.63◦, 21.47◦, 7.25◦, 14.53◦, 22.07◦ and 21◦. These peaks corre-

spond to the W crystalline polymorph of trandolapril, as described

in the literature [15].

The FTIR spectrum of trandolapril is presented in Fig. 2 and

is rather complex, with many sharp peaks, characteristic of each

bond. The carbonyl group appears in 3 instances in trandolapril: in

carboxylic acid, ester group and tertiary amide and therefore, the

peaks in the area of 1600–1800 cm−1 canbe assigned to it. Namely,

the peaks at 1736cm−1, 1706cm−1 and 1654cm−1 are attributed

to C O stretching vibrations of ester, carboxylic acid and amide

groups respectively [16]. The peak at around 1500cm−1, can be

attributed to C N vibrations of the tertiary amide, while the peaks

at 1103–1180 cm−1 and 700–750 cm−1, to C N stretch and N H

wag vibrations of the secondary amine group. Finally, the peakat 3280cm−1 can be assigned to N H stretching vibrations of the

amine. Due to stretching vibrations of C H of aromatic rings some

small peaks appear in the spectral regions of 3000–3100cm−1.

3.2. HSPM investigation

The HSM images that were recorded during heating from 25

to 128 ◦C, cooling from 128 to 90 ◦C, subsequent heating up to

160 ◦C and final cooling to 50◦C are presented in Fig. 3. Crystalline

Fig. 1. XRPD pattern of (a) trandolapril and (b)trandolapril after heating at 180◦

C.



94 E. Roumeli et al. / Thermochimica Acta 539 (2012) 92–99

Fig. 2. FTIR spectrum of (a)trandolapril and(b) trandolaprilafterheating at 180◦C.

polymorph W of trandolapril was completely melted at 128◦C and

then upon cooling it started to crystallize again. From 120 ◦C the

newly formed crystal began to grow and the process was com-

plete at 90 ◦C. The subsequent heating showed that trandolaprilcould not melt at the same temperature anymore. After its first

melting, trandolapril was found to have a much higher melting

point, at 160◦C. Upon thesecond cooling it wasdiscovered that the

morphology, shape and size of trandolapril crystallites was rather

different; round-shaped spherulites had been formed, instead of

the narrow-shaped ones that were observed after the first heating.

3.3. SEM investigation

SEM micrographs (Fig. 4) reveal that trandolapril crystals are of

columnar crystal habit, long and slender with a great variation in

their length. This is also in accordance with literature where it has

been reported that crystals of trandolapril areneedle-like andhave

columnar shape [17].

3.4. Thermal analysis in nitrogen and dry air environments

Physicochemical stability of the active pharmaceutical ingredi-

ent(API)at elevated temperatures is an essential parameter for the

production of a solid dosage formulation. In order to investigate

the thermal stability of trandolapril, DSC and TGA measurements

were carried out in both nitrogen and dry air environments with

a heating rate of 5 ◦C/min. TG/DTG curves of trandolapril heated

under nitrogenenvironment arepresentedin Fig.5a andtheyreveal

that the API remains stable up to 110 ◦C. The first degradation step

occurs between 110 and 178 ◦C and corresponds to a 4.25% mass

Fig. 4. (a and b) SEM microphotographs of trandolapril.

loss. The second degradation step, which results in no residual,beginsat200 ◦Candiscompletedat510 ◦C.TheDSCheatflowcurve,

shown in Fig. 5b, reveals two overlapping endothermic events that

correspond to the melting and the beginning of mass loss of tran-

dolapril, respectively. The melting point of trandolapril, that can

clearly be seen from the heat flow curve in Fig. 5b has an onset at

110 ◦C and peak temperature at 128 ◦C and is in agreement with

literature reported values [17]. The shoulder at 138◦C corresponds

to the beginning of mass loss of trandolapril.

The same measurements were carried out under dry air envi-

ronment and the resulting TG/DTG curves are presented in Fig. 6.

In thiscase, which is rather interesting as the industrial deconstruc-

tion processes of expired drugs usually operate under air flowing

Fig. 3. HSPM images of phase transition during heating process.




Fig. 5. (a) (i) TG, (ii) DTG and (b) DSC curvesof trandolapril heated in N2 environment with rate 5 ◦C/min.

conditions, there are three degradation steps. The first is ranging

between 110and 172◦C and results in a 4.2%massloss. The second

is completed at 412 ◦C resulting in 71% mass loss and the third one

leading to zero residual is completed at 560 ◦C.

Three differences between heating trandolapril under nitrogen

and dry air environments were observed from our results. One

major difference is the number of degradations steps, which is two

in nitrogen and three in dry air environment, implying that theAPI decomposes by different mechanisms in these conditions. This

however, does not apply for the first degradation step, whichis the

same for both of the studied cases. Indeed, the mass loss and heat

flow curves in Figs. 5 and 6, reveal that the first step is the same for

both cases. The second difference is that the second degradation

step begins at lower temperatures and is more rapid under dry air

flow. From these figures it is also clear that degradation under dry

airreaches itsmaximum rate at 320 ◦C,whichis 30◦C lower thanin

nitrogen. Finally, the temperature at which zero residual is reached

is 510 and 560 ◦C for nitrogen and dry air respectively. At 510 ◦C

there is no residue in nitrogen while in dry air there is a residue

of about 7%. Consequently, in order to reach absolutely no residual

in a thermal destruction process, temperatures as high as 510 and

560

◦

C should be reached for nitrogen and dry air environmentsrespectively.

3.5. Investigation of the first degradation step of trandolapril

In order to thoroughly examine the first small mass loss

step of trandolapril, which almost coincides with its melting

and is completed before 180◦C in every case, trandolapril was

heated up to that temperature and then cooled down to room

Fig. 6. (i)TG and(ii) DTGcurvesof trandolapril heated in dryair environmentwith

rate 5◦

C/min.

temperature. Afterwards, thethermally treated sample wasstudied

with DSC, FTIR and XRPD in order to investigate with all com-

plementary methods the reactions taking place during the first

degradation step of trandolapril.

From the obtained heat flow curves (Fig. 7) it is clear that tran-

dolapril undergoes a transformation when heatedup to 180 ◦C that

results in a product with a completely different melting point.

Indeed, from Fig. 7 it can be seen that trandolapril after the firstdegradation step results in a substance with melting point approx-

imately at 160 ◦C, which is 32 ◦C higher than the starting active

substance. That proves that some major changes have happened to

the molecule of trandolapril during its first degradation step.

In Figs. 1 and 2, the XRPD pattern and FTIR spectrum of tran-

dolapril after being heated at 180◦C confirmthat many differences

occurred during its thermal treatment.

From the XRPD pattern (Fig. 1) after the thermal treatment, it

is clear that new peaks appear, while some of the original peaks

of trandolapril are absent. The main peaks in the XRPD patterns

of the heated trandolapril were recorded at 8.14◦, 16.38◦, 22.08◦,

15.44◦, 12.48◦ and12.2◦. This confirms that the APIafter its heating

at 180 ◦C results in a quite different crystal structure.

IntheFTIRspectrum(Fig.2) manypeaks havebeen shifted, somehave been overlapped and some new have appeared. The most

important differences between the spectra of trandolapril pre and

post heating, are located in the 1600–1800cm−1 and 3300cm−1

spectral regions. The peak at 3280cm−1 that is due to vibrations of

the N H bond of the secondary amine is absent from the spectrum

of the heated trandolapril. Therefore by the absence of that char-

acteristic peak, it is revealed that this particular bond is no longer

present in heated trandolapril indicating that no secondary amine

groups remain in the molecule after its heating until 180 ◦C.

Fig. 7. DSCcurves oftrandolapril heated(1) forthe first and(2) forthe secondtime,

both in nitrogen environment, with rate 5◦

C/min.




By focusing on the region 1600–1800cm−1, which corresponds

to carbonyl group vibrations, we notice that the peak at 1736 cm−1

is slightly shifted to higher wavenumbers (1740cm−1), indicating

that the chemical environment of the ester carbonyl group has

changed (Supplementary material). Ascan beseenfromthemolec-

ular structure of trandolapril, this group can form intermolecular

hydrogen bond with the N H group. Therefore, the shifting of the

1736cm−1 peak to higher wavenumbers indicates that this possi-

bility does not exist anymore. Additionally, the absence of weakand broad peak at 1705c m−1, due to the vibrations of the car-

boxylic acid C O, confirms its deformation. Studying further the

area of carboxymethyl vibrations, a new peak at 1670 cm−1 can be

observed whilethe peak at 1654 cm−1 remains. This suggests that a

newamide group wascreatedduringthe thermaltreatment of tran-

dolapril. The difference between the peaks at 1670 and 1654 cm−1,

which can both be attributed to tertiary amide vibrations, can be

assigned to the different chemical environment of the carbonyl

group. So, the differences in the surrounding bonds and chemical

groups seem to induce a shifting to the peaks that are attributed to

amide groups.

Based on the molecular structure changes and weight loss of

trandolapril during melting (4.25% and 4.2%for nitrogenand dry air

environments respectively) and considering the molecular struc-

ture of trandolapril it is reasonable to assume that a reaction

occurred between the secondary amine and the OH of the car-

boxyl group, producing a water molecule, following a cyclization

procedure via nucleophilic attack, as illustrated in Fig. 8. The theo-

retically expected mass loss in such a case would be 4.2%, which is

practically the same with the recorded value.

In details, the methyl group near the carbonyl of the amide, can

be rotated and the secondary amine can easily attack via nucle-

ophilic reaction the carbonyl group of the acid. The new stable

six-member ring is formed, containing a new imide group, while

a water molecule is eliminated as a byproduct of the nucleophilic

attack (cyclization reaction). The chemical description of the new

product is ethyl 2-(3-methyl-1,4-dioxodecahydropyrazino[1,2-

a]indol-2(1H)-yl)-4-phenylbutanoate. It can be described as a

dipiperazine, its molecular formula is C24H32N2O4 and it has amolecular weight of 412.52amu. This compound’s XRPD pattern

and FTIR spectrum are presented in Figs. 1 and 2. The fact that after

heatingtrandolaprilat 180◦C we obtaineda dipiperazine thatcould

possibly be used to design a new formulation with a completely

different pharmaceutical use was happily welcome. Furthermore,

it might lead to the design of an excellent recycling process that

would recover a useful substance from an expired drug. Towards

thisperspective,many other studies including biological evaluation

of the product need to be carried out. This opportunity should not

be overlooked since pharmaceuticals recycling is a much needed

prospective nowadays.

The differences of the crystallites of trandolapril and the new

dipiperazine formed after heating trandolapril at 180◦C can alsobe

Fig. 9. Decomposition mechanism of cyclizised trandolapril.

seenby comparing the correspondingHSPM images fromFig. 3. The

transformation takes place almost simultaneously during melting

and the new spherulites with completely different shape and size

are formed. The melting point of the newly formed dipiperazine, is

close to 160 ◦C as revealed by both DSC thermograms (Fig. 7) and

HSPM images (Fig. 3).

3.6. Py-GC–MS

For the study of decomposition mechanism with Py-GC–MS,

trandolapril is maintained for 2min at 100 ◦C in the pyrolyser

and heated with 20◦C/min till its full decomposition. The exper-

iment was conducted under nitrogen flow. The thermogram shape

(Supplementarymaterial) is similar totheDTGcurve(Fig.5), where

two decomposition peaks were also recorded. A small event is

recorded around 135◦C and the second degradation step around

280 ◦C. Thefirst mass loss step corresponds to gasses with ionmass

18 and is attributed to elimination of water that takes place dur-

ing cyclization of a trandolapril drug and the formation of imide

derivative (Fig. 8). This analysis is in good agreement with the data

already recorded withFTIR spectroscopy. Trandolapril has a molec-

ular weight 430.54g/mol and as can be seen after water removal,

the remaining ion mass is 412 and corresponds to the mass of

cyclizised trandolapril. The second degradation step, which results

in no residual, begins at 180 ◦C and is completed at 450 ◦C.

As can be seen from the mass spectra the weakest part of

cyclizised trandolapril that decomposes first is the ethoxy group

withion mass 45and after this thecarbonyl groupsis removed with

ion mass 28 (Fig. 9). The remaining ion mass after these elimina-

tions is 339.The decompositionafter thisstage is morecomplicated

since a more stablestructure is left. From thegas analysisof decom-

position products it seems that imide ring with the carbonylgroups

and themethylene groups connectedwith benzene ring are broken

Fig. 8. Theproposedreactionof secondary amine with thehydroxyl group of carboxylic acid (cyclizationvia nucleophilic attack).




Fig. 10. (a) TG and (b) DTG curvesof trandolapril for heating rates (1) 5 ◦C/min, (2)

10 ◦C/min, (3)15 ◦C/min and (4) 20 ◦C/min.

and removed. The second remaining imide group is more stable

and thus the connected carbonyl group and the methylene groupswith ion mass 55 are next removed. The most stable molecules

andless volatile arethese of benzene andcyclohexane rings,which

both have ion masses 160 and as can be seen from ion spectra, are

decomposing at the final stage.

3.7. Thermal degradation kinetics of trandolapril

In order to analyze more thoroughly the degradation mecha-

nism of trandolapril W, the kinetic parameters (activation energy E

and pre-exponentialfactor A) andthe conversion function f (˛) need

to be evaluated. In this particular work we focused on the second

degradation step (179–510◦C) as it results in no residue and corre-

sponds to a 96% loss of the initial mass. The relationship between

kinetic parameters andextent of conversion (˛) canbe determinedusingthe mass loss curves. Thedegradation forthisAPI was studied

through non-isothermal measurements at multiple heating rates,

according to the recommendations of the International Confedera-

tion for Thermal Analysis and Calorimetry [18]. In Fig. 10 the mass

lossatdifferentheatingrates,5,10,15and20◦C/min, arepresented.

For the determination of activation energy it is preferable to use

isoconversional methods [19]. Since every isoconversional method

has different error, the use of more than one method can give a

range of values for the activation energy at every particular value

of the degree of degree of conversion, ˛.

The Ozawa–Flynn–Wall (OFW) method is the first one used

[20,21] which involves the measurement of temperature T , cor-

responding to a fixed value of the extent of conversion ˛, from

experiments carried out at different heating rates (ˇ). The OFWmethod is based on the equation:

ln ˇ = −1.052 E

RT + const

The plotof lnˇ vs. 1/T gives the slope−1.0516 E /R by which the

activation energy is calculated.

If the determined activation energy is the same for the various

values of ̨ , theexistence of a single-step reactioncan be concluded

with certainty. On the contrary, a variation of E with degree of

conversion is an indication of a complex reaction mechanism that

invalidates the separationof variables involvedin the OFW analysis

[22]. These complications are significant, especially in the case that

the total reaction involves competitive mechanisms.

Fig. 11. Dependence of activation energy (E ) o n t he e xte nt of con ve rs ion (˛) as

calculatedwith Friedman and OFW methods.

The second isoconversional method applied in this work was

suggested by Friedman [23] and it is a differential method based

on the equation:

ln

ˇd˛

dT

= ln A+ ln f (˛)−

E

RT

Where A is the pre-exponential factor and f (˛) the conversion

function (reaction model). For a constant ˛, the plot of ln(ˇd˛/dT )

vs. (1/T ) obtained from curves recorded at several heating rates,

should be a straight line whose slope gives the value of E . Itis obvi-

ous from this equation that if the function f (˛) is constant for a

particular value of ˛, thenthe sum ln f (˛) +ln A/ˇ, is also constant.

In Fig. 11 the dependence of the activation energy on the dif-

ferent mass conversion values is presented for both methods. The

differences in the values of E calculated by the OFW and Friedman

methods can be explained by a systematic error due to improper

integration. The method of Friedman employs instantaneous rate

values and is therefore, very sensitive to experimental noise. WithOFWmethod, the equation used is derived assuming constant acti-

vation energy, introducing a systematic error in the estimation of

E , in the case E varies with ˛. That error can be estimated by com-

parison with the Friedman analysis results [24].

Both of the used methods present more or less the same trend.

For conversion values up to 0.4, activation energy increases almost

linearly with˛. For higher ˛ values, the activation energy remains

almost stable. This variation indicates that probably a two-step

mechanism will describe the degradation of trandolapril more

accurately. That is in good agreement with the findings of Py-

GC–MS that suggested one relatively easier decomposition process

followed by a more difficult one.

The determination of the reaction model for multiple heating

rates is based on the “model fitting method”. Different kineticmodels were used for the fitting and the conversion range was

0 <˛< 1. Model-fitting methods involve fitting different models to

˛-temperature curves and simultaneously determining the acti-

vation energy E and the pre-exponential factor A. It has recently

been demonstrated that the complementary use of the model-free

method withisoconversionalmethodsfor one stepreactions is very

useful in order to understand the solid-state reaction kinetics [25].

In order to determinethe natureof the mechanisms through the

comparison of the experimental and theoretical data, initially it is

considered that the degradation of the APIcan be described only by

a single mechanism thatcorrespondsto themain massloss, without

presuming the exact mechanism. If the result of the fitting cannot

be considered as acceptable, then the fitting of the experimental

data with a combination of two mechanisms should follow [26].




Fig. 12. Mass loss curves for different heating rates and the corresponding fit-

ting curves with Fn–Fn consecutive mechanisms for heating rates (1) 5 ◦C/min, (2)

10 ◦C/min, (3) 15 ◦C/min and (4) 20◦C/min.

Sixteen different models were tested and the n-th order (Fn)

and n-th order with autocatalysis (Cn) gave the best fit, but in bothcases,divergences appear in the early andthe final stages of degra-

dation, especially in the lower heating rates. The quality of the

fitting, especially in the initial and final degradation stages cannot

be considered as acceptable and taking into account that the ther-

mal degradation of organics is usually very complex, more than

one reaction mechanisms should be considered. That was also sug-

gested by the dependence of the activation energy on the fraction

of mass conversion (Fig. 11).

For the determination of the degradation parameters, two con-

secutivemechanisms wereassumedwhichcorrespond to theinitial

and the main mass loss steps respectively. The Fn mechanism that

was proposed by our preliminary study corresponds to the main

mass loss step while an unknown mechanism corresponds to the

initial mass loss step. In the process of identification by two differ-

entmechanisms, at least six unknown factors are involved, making

the mathematical problem of identification quite complex, with

several possible solutions. For this reason, at this stage of identi-

fication, it is important to limit the scope of the search among all

possible combinations of the widely used models. So, the models

that were used and theircombinations were only those whichhave

already given satisfactory results from the identification through a

singlestep mechanism, such as the reactionmodels Fn,Cn andBna.

The results of the best fitting are presented in Fig. 12 and the

calculated parameters in Table 1. The fit of the experimental data

is rather good for the whole area of mass loss for the studied sam-

ples for the combination of Fn–Fn models. As it can be seen, the

improvement in the quality of the fitting when using two mecha-

nisms instead of one, is profound.

Taking into account the above, the simplest combination of models can be chosen. Thus, Fn–Fn models are the combination

that describes best the degradation of the trandolapril. The acti-

vation energy of each step was calculated 97.4 and 180.0kJ/mol

respectively and the regression coefficient for the selected com-

bination of consecutive steps was 0.999940. This finding is also

in agreement with Py-GC–MS results that were presented above

Table 1

Calculated values of activation energy, pre-exponential factor and exponent n, f or

trandolapril samples.

Model Mechanism E (kJ/mol) log A (s−1) n R

Fn First 97.4 6.33 1.420.999940

Fn Second 180.0 12.37 0.73

and suggested the existence of one relatively easier decomposition

process followed by a more difficult one.

The fact that we were able to combine the actual findings of Py-

GC–MS with the theoretical kinetic studies is very important and

supports the complementary use of such techniques towards the

study of thermal behaviour of pharmaceuticals.

4. Conclusion

The thermal properties of trandolapril were studied in order to

investigate the conditions needed for its safe thermal destruction.

It was found that trandolapril is stable until the onset of melt-

ing (110◦C). In nitrogen and dry air environments it was found

that zero residual is reached at 510 and 550 ◦C respectively. DSC,

HSM, XRPD and FTIR studies confirmed that trandolapril during

heatingjust above its melting point undergoes cyclization via inter-

molecular nucleophilic attack, to form the substituted molecules

of a dipiperazine. From the decomposition mechanism evaluated

with Py-GC–MS it was found that unstable moieties like ethoxy

groups arefirst degradedwhile themost stable likethe benzeneand

cyclohexane groups are at the end. Finally, the activation energy

of the second degradation step was calculated using Friedman’s

and Ozawa, Flynn andWall’s isoconversionalmethods andthe TGA

curves were found to be described best by two consecutive mech-

anisms of n-th order (Fn–Fn). This study is one of the rare cases in

which findings of Py-GC–MS and theoretical calculations of kinetic

parameters of thermal decomposition actually agree, as they both

suggest theparticipation of twosteps in thedecomposition process.

Appendix A. Supplementary data

Supplementary data associated with this article canbe found, in

the online version, at http://dx.doi.org/10.1016/j.tca.2012.04.009.

References

[1] D.R.P. Guay, Trandolapril: a newer angiotensin-converting enzyme inhibitor,

Clin. Ther. 25 (2003) 713–775.[2] S.J. Pickering, Recycling technologies for thermoset composite

materials—current status, Composites Part A 37 (2006) 1206–1215.[3] K. Kümmerer, Drugs in the environment: emission of drugs, diagnostic aids

and disinfectants into wastewater by hospitals in relation to other sources—areview, Chemosphere 45 (2001) 957–969.

[4] D.A. Kuspis, E.P. Krenzelok, What happens to expired medications?A surveyof community medication disposal, Vet. Hum. Toxicol. 38 (1996) 48–49.

[5] O.I. Awad, G.E. Travers, S.A. Mousa, Drug disposal: current recommendationsand environmental concerns,Int. J. Pharm. Res. 2 (2010) 1–6.

[6] J. Abrons, T. Vadala, S. Miller, J. Cerulli, Encouraging safe medication disposalthrough student pharmacist intervention, J. Am. Pharm. Assoc. (JAPhA) 50(2010) 169–173.

[7] C.I. Jarvis, S.M. Seed, M. Silva, K.M. Sullivan, Educational campaign for propermedication disposal, J. Am. Pharm.Assoc. (JAPhA) 49 (2009) 65–68.

[8] C.G. Daughton, T.A. Ternes, Pharmaceuticals and personal care products in theenvironment: agents of subtle change? Environ. Health Perspect. 107 (1999)907–938.

[9] J.B. Ellis, Pharmaceutical and personal care products (PPCPs) in urban receiving

waters, Environ. Pollut. 144 (2006) 184–189(Barking, Essex: 1987).[10] G.R. Boyd, H. Reemtsma, D.a Grimm, S. Mitra, Pharmaceuticals and personal

care products (PPCPs) in surface and treated waters of Louisiana, USA andOntario, Canada, Sci. Total Environ. 311 (2003) 135–149.

[11] M.E. Herring, S.K. Shah, S.K. Shah, A.K. Gupta, Current regulations and modestproposals regarding disposal of unused opioids and other controlled sub-stances, J. Am. Osteopath. Assoc. 108 (2008) 338–343.

[12] D.A. Seehusen, J. Edwards, Patient practices and beliefs concerning disposal of medications,J. Am. Board Family Med. 19 (2006) 542–547.

[13] A. Nguyen, R. Tzianetas, S. Louie, Responsible drug disposal program in NorthVancouver, Can. Med. Assoc. J. 166 (2002) 1252–1253.

[14] A. Shrivastava, K.S. Rathore, N.S. Solanki, A.K. Shrivastava, Pharmaceuticals aspollutants: a threat for pharmacy profession, PDA J. Pharm. Sci. Technol. 2(2010) 163–170.

[15] M. Jaweed, A. Merwade, S. Ansari, A. Saiyad, Novel crystalline polymorph of trandolapril and a process for preparation thereof, Patent WO/2007/026372(2007).

[16] B.C. Smith, Infrared Spectral Interpretation: A Systematic Approach, 1st ed.,

CRC Press,1998.






[17] Z. Makai, J. Bajdik, I. Eros, K. Pintyehodi, Evaluation of the effects of lactose onthe surface properties of alginate coated trandolapril particles prepared by aspray-drying method, Carbohydr. Polym. 74 (2008) 712–716.

[18] S.Vyazovkin, A.K.Burnham, J.M.Criado,L.a.Pérez-Maqueda,C. Popescu,N. Sbir-razzuoli, ICTAC Kinetics Committee recommendations for performing kineticcomputationson thermal analysis data, Thermochim. Acta 520 (2011) 1–19.

[19] K. Chrissafis, Kinetics of thermal degradation of polymers, J. Therm. Anal.Calorim. 95 (2008) 273–283.

[20] T. Ozawa,A newmethodof analyzingthermogravimetric data, Bull. Chem.Soc. Jpn. 38 (1965) 1881–1886.

[21] W.L.A., J.H. Flynn, General treatment of the thermogravimetry of polymers, J.

Res. Natl. Bur. Stand.70 (1966) 487–523.

[22] T. Ozawa, Kinetic analysis of derivative curves in thermal analysis, J. Therm.Anal. 2 (1970) 301–324.

[23] H.L. Friedman, Kinetics of thermal degradation of char-forming plastics fromthermogravimetry. Application to a phenolic plastic, J. Polym. Sci. C: Polym.Symp. 6 (2007) 183–195.

[24] S. Vyazovkin, Modification of the integral isoconversional method to accountfor variation in theactivation energy, J. Comput. Chem. 22 (2001) 178–183.

[25] A. Khawam, D.R. Flanagan, Complementary use of model-free and modelisticmethods in the analysis of solid-state kinetics, J. Phys. Chem. B 109 (2005)10073–10080.

[26] E.Kaisersberger,J. Opfermann,Kinetic evaluationof exothermalreactionsmea-

sured by DSC, Thermochim. Acta 187 (1991) 151–158.

[2012] physicochemical characterization and decomposition kinetics of trandolapril

Documents