Kinetics and mechanism of solid state imidapril hydrochloride degradation and its degradation impurities identification

Article abstract of DOI:10.2478/s11532-013-0212-9

A detailed stability testing of solid state imidapril hydrochloride (IMD) was performed and its degradation products were identified. The analysis was conducted according to ICH guidelines Q1A(R2). Pure IMD samples were exposed to stress conditions of elevated temperature and relative humidity (T = 363 K, RH = 76.4%) in order to accelerate degradation. The regular loss of IMD content with time, and the formation of two degradation impurities were observed. The appropriate reaction rate constants k (for IMD degradation and for the formation of product I and II) were calculated using Prout-Tompkins equation. The obtained degradation products were separated and identified by means of LC-MS technique. Based on the obtained m/z values, the masses and the structures of the formed degradation impurities were established. Also IMD degradation scheme was constructed. It was demonstrated that under the applied analytical conditions, IMD degradation follows an autocatalytic reaction model with the rate constant k = (4.764 ± 0.34)×10 ^-6 s ^-1 and with the parallel formation of two degradation products: imidaprilat and the diketopiperazine derivative. The obtained experimental results are in agreement with IMD degradation pathways proposed theoretically. [Figure not available: see fulltext.]

Full text of DOI:10.2478/s11532-013-0212-9

Cent. Eur. J. Chem. • 11(5) • 2013 • 754-762
DOI: 10.2478/s11532-013-0212-9
Central European Journal of Chemistry
Kinetics and mechanism of solid state
imidapril hydrochloride degradation
and its degradation impurities identification
Research Article
Katarzyna Regulska1,2*, Beata Stanisz2#
1The Oncology Center of Wielkopolska,
61-866 Poznan, Poland
2Department of Pharmaceutical Chemistry,
Poznan University of Medical Sciences,
60-780 Poznan, Poland
Received 2 October 2012; Accepted 3 January 2013
Abstract:
A detailed stability testing of solid state imidapril hydrochloride (IMD) was performed and its degradation products were identified.
The analysis was conducted according to ICH guidelines Q1A(R2). Pure IMD samples were exposed to stress conditions of elevated
temperature and relative humidity (T = 363 K, RH = 76.4%) in order to accelerate degradation. The regular loss of IMD content with
time, and the formation of two degradation impurities were observed. The appropriate reaction rate constants k (for IMD degradation and
for the formation of product I and II) were calculated using Prout-Tompkins equation. The obtained degradation products were separated
and identified by means of LC-MS technique. Based on the obtained m/z values, the masses and the structures of the formed degradation
impurities were established. Also IMD degradation scheme was constructed. It was demonstrated that under the applied analytical
conditions, IMD degradation follows an autocatalytic reaction model with the rate constant k = (4.764 ± 0.34)×10-6 s-1 and with the
parallel formation of two degradation products: imidaprilat and the diketopiperazine derivative. The obtained experimental results are in
agreement with IMD degradation pathways proposed theoretically.
Keywords: Imidapril hydrochloride • Stability in solid state • LC-MS • Degradation impurities
© Versita Sp. z o.o.
1. Introduction
203ºC [4]. Solid state IMD is chemically unstable
under stress conditions. It undergoes a temperature-
and humidity-dependent degradation according to an
autocatalytic reaction model, meaning that the reaction
product is also its catalyst [5]. The kinetic order of IMD
degradation changes in the presence of magnesium
stearate (MgS) which is a common lubricating substance
used in the pharmaceutical industry as tablet excipient.
The experimental data show that in the binary mixture
MgS/IMD (1:1 w/w), its decomposition follows first-order
kinetics yielding one major product verified as imidaprilat
[6]. Another probable path of IMD decomposition is an
intra-molecular cyclization between the two neighboring
amino-acids with the formation of a diketopiperazine
derivative (DKP), which has been recognized as a
degradationpatternofotherstructurally-relateddipeptide-
Imidapril hydrochloride (IMD), chemically named
as ((-)-(4S)-3-[2(S)-[N-[1(S)-(ethoxycarbonyl)-
3-phenylpropyl]amino]propionyl]-1-methyl-2-
oxoimidazolidine-4-carboxylic acid hydrochloride
(Fig. 1), is a dipeptide-type, dicarboxylate-containing,
non-sulfhydryl angiotensin converting enzyme
inhibitor (ACE-I), which has been widely used as an
antihypertensive agent in the treatment of essential
hypertension, chronic congestive heart failure, and type
1 diabetic nephropathy [1,2]. After oral administration
it is metabolized by ethyl ester bond hydrolysis to the
active metabolite - imidaprilat [3]. At room temperature
it occurs in a form of white crystalline powder, soluble
in methanol and water, with the melting point about
* E-mail: katarzyna.regulska@wco.pl
# E-mail: bstanisz@ump.edu.pl
754

K. Regulska, B. Stanisz et al.
2.2. Apparatus
2.2.1. High-Pressure Liquid Chromatographic method
Shimadzu liquid chromatograph consisting of Rheodyne
7125, 100 µL fixed loop injector, UV-VIS SPO-6AV
detector, LC-6A pump and C-RGA chromatopac
integrator was used under the following operating
conditions: stationary phase
-
LiChrospher 100
RP-18 (size 5 µm) 250×4 mm I.D column maintained at
ambient temperature, and mobile phase - a mixture of
Figure 1. Molecular structure of imidapril hydrochloride (IMD).
type ACE-I, i.e., moexipril hydrochloride [6,7], enalapril acetonitrile and phosphate buffer (0.001 mol L-1 adjusted
maleate [6,8] and quinapril hydrochloride [9]. There to pH 2.0 with ortho-phosphoric acid) (30:70 v/v).
are, however, no studies analyzing main degradation Chromatographic separation was achieved isocratically
pathways of pure IMD in solid state.
at a flow rate of 1.2 mL min-1. The detector wavelength
Identification of drug degradation impurities is was set at 216 nm [5] and the injection volume was
a basic requirement for regulatory approval of any 25 µL. The mobile phase had been filtered through
pharmaceutical intended for human use [10-12]. 0.22 µm filter and degassed by ultrasound prior to
The recommended analytical approach involves the use. The technique employing an internal standard
conduction of forced degradation or stress testing (a 0.020% methanolic solution of benzocaine; IS)
described in ICH Q1A(R2) guideline [13]. An important was applied.
aspect of drug stability analysis is the selection of an
appropriate analytical method that fulfills the established 2.2.2. Liquid Chromatography/Electrospay Ionization-
validity criteria, such as: selectivity, sensitivity, precision
Mass Spectrometry System
and linearity. There are several strategies for IMD The LC-MS system consisted of a WatersAlliance HPLC
determination described in the literature, including: gas equipped with a Photodiode Array Detector Waters
chromatography-mass spectrometry (GC-MS) [14] and PDA 996 coupled to a Single Quadruple Mass Detector
radioimmunoassay [15] for its pharmacokinetic studies, Waters Micromass ZQ 2000. The IMD degradation
and single liquid chromatography-mass spectrometry products were separated on a LiChrospher 100 RP-18
(LC-MS) [4,6], reversed phase high performance (size 10 µm, 250×4 mm) column at temperature 30°C.
liquid chromatography (RP-HPLC) and first derivative The mobile phase (methanol – water – formaldehyde
ultraviolet spectrophotometry (1D-UV) for IMD stability (49:50:0.5 v/v/v)) had been filtered through 0.22 µm
analysis in pure, and in binary mixtures with MgS in filter, degassed by ultrasound prior to use and pumped
solid state [5,6]. Thus, for the identification of solid-state at a flow rate of 0.5 mL min-1. The injection volume was
IMD degradation products RP-HPLC and LC-MS were 100 µL.
selected mainly because of their established applicability
for IMD determination [5,6] and also due to their 2.3. RP-HPLC mobile phase and IS optimization
relatively low costs, simplicity, common accessibility and Three concentrations of acetonitrile: 20, 30, 40%, mixed
applicability for the analysis of a wide range of various with phosphate buffer (0.001 mol L-1), adjusted to pH
drug products [5,6,16-19].
2.00 with 88% ortho-phosphoric acid, were used as
mobile phase for chromatographic separation of IMD
degradation products under the conditions described
above. After the selection of the optimum mobile phase
composition the flow rate was adjusted by the analysis
of three different pump working modes: 1.0 mL min-1,
1.2 mL min-1, 1.5 mL min-1.
The investigated samples were injected onto the
chromatographic column manually. For this reason the
technique employing an internal standard had to be
used in order to avoid an error inherent during sample
injection and eliminate random errors. The following
internal standards were tested for their applicability:
antazoline hydrochloride, naphazoline, oxymetazoline,
teofiline and benzocaine.
2. Experimental procedure
2.1. Chemicals
Imidapril hydrochloride was kindly provided by
Jeleniogorskie Zaklady Farmaceutyczne (Jelenia Gora,
Poland). Benzocaine was obtained from Novartis (Basel,
Switzerland). Analytical grade potassium phosphate
monobasic,natriumchloratumandortho-phosphoricacid
were purchased from POCh S.A. (Gliwice, Poland) and
HPLC grade methanol and acetonitrile were supplied by
Merck KGaA (Darmstadt, Germany). Freshly bidistilled
water was used.
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Kinetics and mechanism of solid state imidapril hydrochloride
degradation and its degradation impurities identification
2.4. Validation of RP-HPLC method
2.5. Kinetic studies
The RP-HPLC method was validated according to the The study was conducted under the following stress
International Conference on Harmonisation Guidelines conditions: temperature 363 K and relative humidity
[21].
76.4%. Pure IMD samples (0.0100 g) were weighed,
placed into desiccators filled with saturated aqueous
solution of sodium chloride (which maintained the
2.4.1. Linearity
Stock solution was freshly prepared by dissolving desired humidity level throughout analysis) and
40.0 mg of IMD in 100.0 mL of methanol. Ten standard heated for different periods of time in order to induce
solutions (n=10) at the following concentrations: 0.002, degradation. After heating the samples were cooled
0.004, 0.008, 0.012, 0.016, 0.020, 0.028, 0.032, 0.036, to room temperature, dissolved in bidistilled water,
0.040% were obtained by diluting the stock solution with quantitatively transferred into volumetric flasks and
methanol. Each standard solution was mixed with 1.0 mL made up to a total volume of 25.0 mL with methanol.
of IS (a methanolic solution benzocaine) at 1:1 (v/v) ratio The aliquots of 1.0 mL of the so obtained solutions (after
and immediately injected onto the chromatographic filtration if necessary) were mixed with 1.0 mL of IS and
column. Three measurements were performed for each chromatographed according to the validated RP-HPLC
concentration and for linearity assessment the mean protocol. The measured relative peak areas (pi/pIS) were
value from triplicate analysis for each concentration plotted versus time:
was used. The obtained relative IMD peak areas (pi/pIS)
were measured and plotted against corresponding IMD
concentrations:
pi/pIS = f(t);
(4)
where: pi is the area of IMD signal, pIS is the area of IS
(1) signal and t is time.
pi/pIS = f(c);
where: pi is the area of IMD signal and pIS is the area 2.6. Identification of IMD degradation products
of IS signal. The appropriate regression equation was The identification of IMD degradation products was
computed using least square method.
performed by means of LC-MS method. The electrospray
(ESI) ionization, which is known as a soft ionization
technique, was applied. The mass spectrometer was
2.4.2. Precision and accuracy
The intra-day precision and accuracy were investigated run in positive (ES+) and negative (ES-) ionization modes
by eight replicate analysis of IMD samples at the in the mass range of m/z 100 - 1000. The molecular
concentration of 0.0160% on the same analytical run. ions were identified and the corresponding mass-to-
The inter-day precision and accuracy were assayed charge ratios (m/z) were compared to the theoretically-
after repeated analysis of eight IMD samples at the calculated molecular masses in order to confirm the
concentration of 0.0200% performed on two different presence of the predicted degradation impurities in the
days over a period of a week. The inter- and intra-day degraded IMD sample.
coefficient of variation (CV) and an average recovery
were calculated.
3. Results and discussion
2.4.3. Limit of detection (LOD) and limit of quantitation
(LOQ)
3.1. Method development and validation
The LOD and LOQ were calculated on the basis of the RP-HPLC is an established approach to stability
regression equation (available in Table 2) using the testing of solid state IMD [5,6], however, the previously
following formulae:
LOD= 3.3Sy/a;
LOQ= 10Sy/a;
described mobile phase, consisting of acetonitrile –
methanol – phosphate buffer (0.001 mol L-1, adjusted
(2) to pH 2.0 by ortho-phosphoric acid) (60:10:30 v/v/v) [5],
failed to provide an acceptable separation of IMD and its
(3)
degradation products (Table 1, Fig. 2A). Therefore, an
optimization of the analytical conditions was necessary
where: Sy is the standard deviation of the and to that end the following factors were evaluated:
calibration curve and a is the slope of the calibration concentration of an organic component in a mobile
curve.
phase, the mobile phase flow rate and the internal
756

K. Regulska, B. Stanisz et al.
Table 1. Parameters of RP-HPLC separation efficiency.
Mobile phase
acetonitrile – methanol – phosphate
acetonitrile – phosphate buffer pH
2.00 (30:70 v/v)
flow rate 1.2 mL min-1
buffer pH 2.00 (60:10:30 v/v/v)
Compound
Product I
Product II
IMD
Number of theoretical plates (n)
2172
2836
4986
11364
1064
2015
6382
4533
IS
R
I-II = 0.59
RII-IMD = 2.36 RIMD-IS = 1,48
RI-IS = 3.73 RII-IS = 3.54
RI-IMD = 3.14
RI-II = 1.18
RII-IMD = 3.30 RIMD-IS = 2.12
RI-IS = 2.66 RII-IS = 1.48
RI-IMD = 4.28
Resolution factor (R)
RP-HPLC method were within the acceptance criteria of
>2000 and >1.5, respectively, confirming good column
efficiency and optimum mobile phase composition [20].
The developed RP-HPLC protocol was subsequently
validated and results are summarized in Table 2. A high
value of correlation coefficient r = 0.999 indicated a
strong linear relationship between the measured signal
and the corresponding concentration. The average
recovery obtained for intra-day and inter-day analysis
was 99.37% and 100.5%, respectively and the coefficient
of variation was less than 1.55% suggesting a good
precision and accuracy of the method. The employed
chromatographic system allowed a complete separation
of IMD, its degradation products and IS, confirming
method’s good selectivity. Well-resolved, sharp
peaks were observed at the following retention times:
tR = 12 min for IMD, tR = 7 min for IS, tR = 3 and 5 min for
two degradation products (Fig. 2B).
3.2. Kinetics of IMD degradation in solid state
The kinetic order of solid-state IMD degradation was
established by its content determination in the degraded
samples stored under stress conditions over different
time intervals. The relative peak areas pi/pIS (where pi is
IMD peak area and pIS is IS peak area) were measured
and plotted versus time to produce the sigmoid kinetic
curve pi/pIS = f(t) (Fig. 3A) characterized by induction,
acceleration and termination period. This confirmed an
autocatalytic character of the observed reaction and
therefore the calculation of its kinetic parameters was
performed by the use of Prout-Tompkins equation [22]:
Comparison of quality of HPLC chromatograms obtained
for the degraded IMD sample under various analytical
conditions. (A) Mobile phase consisting of acetonitrile
Figure 2.
-1
- methanol – phosphate buffer (0.001 mol L , adjusted
to pH 2.0 with ortho-phosphoric acid) (60:10:30), mobile
phase flow rate: 1.0 mL min-1; (B) Mobile phase consisting
-1
of acetonitrile – phosphate buffer (0.001 mol L , adjusted
to pH 2.0 with ortho-phosphoric acid) (30:70 v/v), mobile
phase flow rate: 1.2 mL min-1.
standard matching. The highest-quality chromatograms
were achieved for a mixture of acetonitrile and phosphate
buffer (30:70 v/v) at the flow rate of 1.2 mL min-1 with
benzocaine as IS (tR = 7 min) (Fig. 2B) and these
parameters were accepted for further analysis. The
efficiencyofthedevelopedanalyticalsystemwasassayed
and compared with the previously-described one. The
results are shown in Table 1. The number of theoretical
plates (n) and the resolution factor (R) for the optimized
ln {(pi/pIS)t/[(pi/pIS)0 – (pi/pIS)t])} = C – k t;
(5)
where: (pi/pIS)t and (pi/pIS)0 are relative IMD peak areas
in time t and t0 respectively, t is time, k is reaction rate
constant and C is induction period (Fig. 3B). The results
are demonstrated in Table 3.
757

Kinetics and mechanism of solid state imidapril hydrochloride
degradation and its degradation impurities identification
Table 2. Validation report for the RP-HPLC method.
Linearity range
Regression equation y = ax + b
Slope a ± ∆a
Standard deviation of the slope
Intercept b ± ∆b
Standard deviation of the intercept
Correlation coefficient
n
55.31 ± 1.87
0.84
0.036 ± 0.047
0.021
0.998799207
10
Sy
0.035
LOD = 3.3 Sy/a
0.0021
LOQ = 10 Sy/a
0.0064
Statistical assessment of calibration curve y = ax + b
Intercept b was evaluated by Student’s- t test using t = b/Sa equation. Experimental t =1.71 was less than the corresponding theoretical one
t
α0.05 = 2.201 meaning that b is statistically insignificant and calibration line passes through zero according to the equation y = ax.
Precision and accuracy
Intra-day
Nominal concentration (%)
Assayed concentration (%)
Average recovery (%)
0.0160
0.0159 ± 1.01 10-4
99.37
Standard deviation
1.42 10-4
Coefficient of variation (%)
0.890
Inter-day
Nominal concentration (%)
Assayed concentration (%)
Average recovery (%)
Standard deviation
0.0200
0.0201 ± 2.22 10-4
100.5
3.11 10-4
Coefficient of variation (%)
1.55
Figure 3.
(A) pi/pIS = f(t) plot for IMD degradation [sub] and for the formation of IMD degradation products [prod I, prod II] in solid state
(T = 363 K, RH = 76.4%). (B) Semi-logarithmic plot of solid state IMD degradation (pi/pIS)t/[(pi/pIS)0 – (pi/pIS)t] = f(t) [sub] and its
degradation products formation [(pi/pIS)∞ -( pi/pIS)t]/ (pi/pIS )t = f(t) for products [prod I,II].
3.3. Kinetics of IMD degradation impurities
kinetic curves (Fig. 3B). The formation rate constants (k)
for both products were calculated on the basis of Prout-
Tompkins equation [22]:
formation in solid state
The kinetics of IMD degradation impurities formation
was investigated by the determination of their contents
in the degraded IMD samples using RP-HPLC. The
appropriate plots for product I and product II were
established:
ln {[(pi/pIS)∞ -(pi/pIS)t]/ (pi/pIS )t} = -kt + C
(7)
where: pi –peak area of product I or II, pIS – peak area
of IS, k –the formation rate constant of product I or II,
t – time, C – induction period. The (pi/pIS)∞ was assumed
0.75 for product I and 0.25 for product II since these
are the points in which the appropriate kinetic curves
achieve their plateau and therefore they can be
considered as the concentrations in the infinite time
pi/pIS = f(t)
(6)
where pi is the peak area of product I or II and pIS is
the peak area of IS, t is time (Fig. 3A). In both cases
autocatalysis was observed as indicated by sigmoid
758

K. Regulska, B. Stanisz et al.
Table 3. Parameters of IMD degradation and its degradation products formation under T = 363 K and RH = 76.4%.
Compound
IMD
Product I
Product II
Slope of a straight line
Correlation coefficient
Relative deviation
-0.412 ± 0.03*
-0,411± 0,012**
-0.413 ±0.029**
0.997
0.139
0.999
0.195
0.996
0.136
Number of samples
Reaction rate constant (s-1
11
11
11
)
(4.764 ± 0.34) 10-6
(4.760 ±0.14) 10-6
(4.785 ±0.33) 10-6
Statistical assessment
F0.05 (n1-1; n2-2) = 2.98
t (n1 + n2 -2) = 2.086
1.40
1.48
0.052 10-6
0.318 10-6
*ln {(pi/pIS)t/[(pi/pIS)0 – (pi/pIS)t]} = f(t)
**ln {[(pi/pIS)∞ -(pi/pIS)t]/ (pi/pIS )t} = f(t)
Figure 4. LC-MS chromatogram for IMD after 6 h of heating under T = 363 K and RH = 76.4% (A) detected by UV absorption using mass
spectrometric total ion current (TIC); (B) acquired in negative ES- TIC mode; (C) acquired in positive ES+ TIC mode.
(Fig. 3A). The obtained k values were compared using
3.4. Identification of IMD degradation products
F-Snedecor and Student’s t-tests (Table 3) and since
they were not statistically different it was concluded that
both products were formed simultaneously according to
parallel reaction kinetics.
The identification of IMD degradation products
was performed by means of LC-MS method. The
chromatogram obtained for an undegraded IMD
demonstrated only one peak at tR = 6.90 min, which
759

Kinetics and mechanism of solid state imidapril hydrochloride
degradation and its degradation impurities identification
Figure 5. ES+ mass spectrum (A) for IMD degradation product I, (B) for IMD degradation product II and (C) for pure IMD.
Figure 6. ES- mass spectrum (A) for IMD degradation product I, (B) for IMD degradation product II and (C) for pure IMD.
760

K. Regulska, B. Stanisz et al.
Table 4. The m/z values of [M+H]+ and [M-H]- for IMD and its degradation impurities in solid state.
Compound
Chemical
formula
Calculated
molecular mass
Observed
m/z value, ES+
Observed
m/z value, ES-
IMD
C20H27N3O6
C20H25N3O5
C18H23N3O6
405
387
377
406
386
378
404
386
376
Product I
(DKP)
Product II (Imidaprilat)
Figure 7. The proposed scheme for solid state IMD degradation under the conditions of T = 363 K, RH = 76.4%.
confirmed high purity of the analyzed sample. In the diacidic derivative of IMD (molecular mass 377) formed
chromatograms achieved for IMD samples exposed to by its ester bond hydrolysis. These results are listed
six-hour-stress conditions (T = 363 K, RH = 76.4%), in Table 4. The detailed fragmentation patterns of the
two additional peaks appeared: at tR ≈ 4.50 min and at investigated compounds were not analyzed due to a
tR ≈5.50min, andtheywereattributedtoIMDdegradation very limited fragmentation obtained under the applied
impurities (Figs. 4A, 4B, 4C).
analytical conditions. Based on the above findings the
The application of soft ionization technique in MS following paths of solid state IMD degradation could be
analysis enabled an unambiguous verification of the proposed (Fig. 7).
pseudo-molecular ions type [M+H]+ or [M-H]– as the
most abundant signals. Peaks at m/z = 404 [M-H]– and
m/z = 406 [M+H] + matched with the molecular mass of
pure IMD. Peaks at m/z = 386 [M-H]– were attributed to
4. Conclusion
The process of IMD degradation follows an autocatalytic
reaction model with the rate constant k = (4.764
± 0.34)×10-6 s-1 and with the formation of two major
degradation impurities: imidaprilat, formed by IMD ethyl
ester bond hydrolysis, and DKP formed by IMD intra-
product I which was verified as DKP (molecular mass
387) formed by IMD intra-molecular cyclization. For
product II the following m/z values were observed: 378
forprotonatedmolecule[M+H]+ and376fordeprotonated
molecule [M-H]– (Figs. 5,6), which corresponded to a
761

Kinetics and mechanism of solid state imidapril hydrochloride
degradation and its degradation impurities identification
molecular cyclization. The corresponding formation organic component in a mobile phase and by the flow
rate constants were: k = (4.785 ±0.33)×10-6 s-1) for rate of a mobile phase. The optimized and validated
imidaprilat, and k = (4.760 ±0.14)×10-6 s-1) for DKP. stability-indicating RP-HPLC assay method was able to
The difference between these values was statistically separate IMD from its degradation impurities, and the
insignificant suggesting the simultaneous formation degradation impurities from each other with satisfactory
of these compounds. Imidaprilat and DKP are also selectivity, precision, accuracy and linearity, which
considered to be present in the formulated drug stored makes it appropriate for the kinetic analysis of IMD
under the conditions of ambient temperature and decomposition and its degradation products formation.
relative humidity 40-60%, which might have a negative Furthermore, the identification of IMD degradation
clinical effect on drug’s efficiency and safety. Imidaprilat impurities can be successfully performed by means of
is an active metabolite of IMD which is poorly absorbed LC-MS method with ESI ionization, which, provides an
after oral administration. Thus the hydrolysis of IMD to unambiguous molecular weight information.
imidaprilat may impair drug’s bioavailability. Moreover,
there are no data on DKP pharmacological properties.
For all these reasons the clinical importance of our
findings needs to be further assessed in appropriate
Acknowledgement
toxicological and pharmacokinetic studies.
The optimum HPLC resolution of IMD and its
degradation products was influenced by the ratio of
The LC-MS analysis was performed in the Faculty
of Chemistry at A. Mickiewicz University in Poznan,
Poland.
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762