UV derivative spectrophotometric study of the photochemical degradation of nisoldipine

Article abstract of DOI:10.1016/S0014-827X(00)00004-5

The photodecomposition of nisoldipine ((±)3-isobutyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate), whereby its 4-(2-nitrosophenyl) pyridine analogue is obtained as the photolytic product, was investigated under daylight exposure by means of UV derivative spectrophotometry. The optimal instrumental parameters (120 nm/min scan speed; 2 nm slit width; Δλ=10 nm and 5 s response time) for analogue derivative spectra were established for amplitudes ¹D₂₈₅ and ²D₂₉₁ (measured to the baseline) of the nitroso analogue assay, as well as for ¹D₃₈₆ of the parent compound-nisoldipine assay. Using the first-order derivative spectrum, the minimum detectable amount of nitroso analogue in the presence of nisoldipine was equivalent to an impurity level of 5% and by the second-order derivative spectrum, the determination limit was equivalent to an impurity level of 2%. The degradation of nisoldipine followed within 30 days and the calculated maximal degradation rate was 1.6% per day for nisoldipine raw material, but significantly lower values of 0.19 and 0.15% per day were obtained for Nisoldin tablets (10 and 5 mg, respectively). Copyright (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(00)00004-5

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 128–133
UV derivative spectrophotometric study of the photochemical
degradation of nisoldipine
Valentina Marinkovic a, Danica Agbaba b,*, Katarina Karljikovic-Rajic b,
Jozef Comor c, Dobrila Zivanov-Stakic b
a Zdra6lje Pharmaceutical and Chemical Industry, Quality Control Sector, 16000 Lesko6ac, Yugosla6ia
b Faculty of Pharmacy, Department of Pharmaceutical and Analytical Chemistry, Uni6ersity of Belgrade, PO Box 146,
11221 Belgrade, Yugosla6ia
c Vinca Institute of Nuclear Sciences, PO Box 522, 11001 Belgrade, Yugosla6ia
Received 29 July 1999; accepted 30 December 1999
Abstract
The photodecomposition of nisoldipine ((9)3-isobutyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicar-
boxylate), whereby its 4-(2-nitrosophenyl) pyridine analogue is obtained as the photolytic product, was investigated under daylight
exposure by means of UV derivative spectrophotometry. The optimal instrumental parameters (120 nm/min scan speed; 2 nm slit
1
2
width; Du=10 nm and 5 s response time) for analogue derivative spectra were established for amplitudes D285 and D291
1
(measured to the baseline) of the nitroso analogue assay, as well as for D386 of the parent compound–nisoldipine assay. Using
the first-order derivative spectrum, the minimum detectable amount of nitroso analogue in the presence of nisoldipine was
equivalent to an impurity level of 5% and by the second-order derivative spectrum, the determination limit was equivalent to an
impurity level of 2%. The degradation of nisoldipine followed within 30 days and the calculated maximal degradation rate was
1.6% per day for nisoldipine raw material, but significantly lower values of 0.19 and 0.15% per day were obtained for Nisoldin®
tablets (10 and 5 mg, respectively). © 2000 Elsevier Science S.A. All rights reserved.
Keywords: Nisoldipine; Photodegradation; Derivative UV spectrophotometry
One is the nitrophenylpyridine product (III) elicited
by ultraviolet light, and the other the ni-
1. Introduction
trosophenylpyridine product (II) caused by daylight
irradiation. An electrochemical study of nisoldipine
photodegradation has been published recently [7], as
well as an analysis of its analytical application in
pharmaceutical forms.
Stability of nisoldipine in organic solutions was stud-
ied by GC [8] and dual-wavelength UV spectrophoto-
metric methods [9], as well as in inclusion complexes
with b-cyclodextrin [10,11].
The literature data with respect to this group of
drugs also concern the assay of nifedipine tablets using
first-order UV spectrophotometry [12], determination
of nifedipine in a mixture with atenolol by UV deriva-
tive spectrophotometry and gas chromatography [13],
as well as gas chromatographic and the third-order UV
derivative determination of nitrendipine and its
photodegradation product [14].
Nisoldipine ((9)3-isobutyl-5-methyl-1,4-dihydro-2,6-
dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate)
is
a
calcium-channel-blocking 1,4-dihydropyridine
derivative, with nonidentical ester functions, which has
been developed as an antihypertensive and antianginal
drug [1].
The exposure of some 1,4-dihydropyridines to light
leads to photodecomposition [2–6]. The chemical
changes in the irradiated molecule of nisoldipine in-
volve the oxidation of the dihydropyridine ring to a
pyridine ring, and the reduction of the aromatic nitro
group to a nitroso group. Depending on the source of
irradiation, two photodegradation products of nisoldip-
ine (I) are obtained (Scheme 1).
* Corresponding author.
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00004-5

V. Marinko6ic et al. / Il Farmaco 55 (2000) 128–133
129
Recently, the photochemical degradation of nisoldip-
2.2. Assay
ine in UV light, in ethanol solutions, was investigated
by means of HPLC and MS [15], but no study has been
reported considering the stability and degradation of
solid nisoldipine. The objective of the present work was
the photodecomposition study of nisoldipine raw mate-
rial and nisoldipine film-coated tablets, after exposure
to daylight, by means of UV derivative spectrophoto-
metry. The application of derivative techniques to spec-
troscopy is very useful when signal overlap or
interference exists and it offers a powerful tool for both
qualitative and quantitative analysis of mixtures in
pharmaceuticals and biomedical analysis.
2.2.1. Stock solutions
Nisoldipine (0.1 mg/ml) and its nitroso analogue
standard substance in methanol was used.
2.2.2. Calibration solutions
A series of six standard solutions of nisoldipine were
prepared by dilution of the corresponding stock solu-
tion to obtain a concentration range of 1–10 mg/ml and
were used in the first-order derivative spectrophotomet-
ric assay.
A series of six standard solutions of nitroso analogue
were prepared by diluting the corresponding stock solu-
tion to obtain the concentration ranges 0.4–20 mg/ml
and 0.2–5 mg/ml, which were used in the second-order
and first-order derivative spectrophotometric assays,
respectively.
2. Experimental
2.1. Material and methods
2.2.3. Sample preparation
Nisoldipine raw material (1 g), distributed in a thin
layer (B1 mm) on a small Petri dish, was exposed to
daylight for 30 days at room temperature (25°C). Nisol-
din® tablets were kept in a glass container and also
exposed to daylight for the same amount of time.
Samples were taken from the Petri dish every 5 days
and analyzed immediately. A quantity of powdered
tablets containing 10 mg of nisoldipine was extracted
with methanol and the final concentrations were ap-
proximately 20 and 5 mg/ml for the second-order and
first-order derivative spectrophotometric assays, respec-
tively. The same concentrations for the corresponding
derivative spectra of standard nisoldipine samples were
analyzed.
2.1.1. Chemicals
Nisoldipine ((9)3-isobutyl-5-methyl-1,4-dihydro-2,6-
dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate)
and its nitroso analogue ((9)3-isobutyl-5-methyl-2,6-
dimethyl-4-(2-nitrosophenyl)-pyridine-3,5-dicarboxylate),
were obtained as standard substances from Promed
(Prague, Czech Republic). Nisoldipine raw material and
Nisoldin® film-coated tablets containing 5 and 10 mg of
nisoldipine were obtained from Slaviamed (Belgrade,
Yugoslavia). Methanol p.a. from E. Merck (Darmstadt,
Germany) was used as solvent.
2.1.2. Apparatus
A Perkin–Elmer Lambda-15 UV–Vis spectrophoto-
meter (San Jose, USA) equipped with 10 mm quartz
cuvettes was used. The instrumental parameters were
120 nm/min scan speed, 2 nm slit width, Du=10 nm
and response (time constant) 5 s.
2.2.4. Procedure
For analysis of nisoldipine and its nitroso analogue,
zero-order spectra were recorded against the solvent in
the wavelength range 250–350 nm. The first-order
Scheme 1. Photodegradation products of nisoldipine (I) under ultraviolet and daylight exposure, nitrophenylpyridine (III) and ni-
trosophenylpyridine (II).

130
V. Marinko6ic et al. / Il Farmaco 55 (2000) 128–133
3. Results and discussion
3.1. Spectrophotometric analysis
In the routine analysis of nisoldipine raw material, as
well as in the assay of dosage forms, the conventional
UV spectrophotometric method at 360 nm is used as
the industrial reference method (Slaviamed, Belgrade,
Yugoslavia). The structural similarity of the nitroso
analogue and the parent compound leads to difficulty
in the conventional UV spectrophotometric methods of
analysis for this group of compounds, as their UV
spectra overlap extensively, as seen for nisoldipine
(curve 2) and its nitroso analogue (curve 1) in Fig. 1.
This invalidates the usual compendial procedure of
using absorbance measurement at a single wavelength
for nitroso analogue determination, and also because
nisoldipine in dosage forms is in a large excess with
respect to its degradation product, nitroso analogue.
The use of derivative spectroscopy for quantitative
analysis of closely related analytes requires the careful
selection of the appropriate analytical bands, the ap-
propriate derivative order and optimization of all rele-
vant instrumental parameters. The transformation to
the first-order derivative spectra of nisoldipine and its
nitroso analogue (Fig. 2) indicates the possibility for
the simultaneous assay of both compounds. In the
wavelength range 274–290 nm the first-order derivative
spectrum of nisoldipine showed no significant signal,
since the zeroth-order spectrum of nisoldipine in this
wavelength range (minimum of spectra) has a constant
absorbance value. The effect of the first-derivative tech-
nique in discriminating against a constant nisoldipine
interference for nitroso analogue determination is suffi-
cient. For nisoldipine concentrations lower than 5 mg/
ml, the spectrum was essentially zero (Fig. 2(a), curve
2). In this part of the first-order derivative spectrum,
Fig. 1. Zeroth-order UV spectra of nisoldipine (20 mg/ml; curve 2);
nitroso analogue (20 mg/ml; curve 1) and their binary mixture of the
same concentrations (curve 3).
Fig. 2. First-order derivative UV spectra of: nisoldipine (curve 2);
nitroso analogue (curve 1) and their binary mixture of the same
concentrations (curve 3). Concentrations of nisoldipine and its ni-
troso analogue were 5 and 1 mg/ml and 7.5 and 1 mg/ml for (a) and
(b) respectively.
1
the existence of the amplitude D285 of nitroso analogue
was substantial (Fig. 2(a), curve 1). The value of the
1
derivative spectrum, obtained by analogue differentia-
tion, is utilized for the simultaneous determination of
nisoldipine and nitroso analogue using amplitudes 1D386
amplitude D285 obtained for a binary mixture of nisol-
dipine and its nitroso analogue was the same as the
corresponding D285 of the standard nitroso analogue
1
1
and D285, respectively. The corresponding amplitude
solution, confirming that the selected amplitude is due
only to the nitroso analogue concentration (Fig. 2(a),
curves 1 and 3). This derivative order is limited to the
parent compound concentration (up to 5 mg/ml) that is
presented in Fig. 2(b). For nisoldipine concentrations
higher than 5 mg/ml the first-order derivative spectrum
(Fig. 2(b), curve 2) shows positive values in the wave-
length range 270–300 nm. Due to this, the difference
2D291 is used for determination of the nitroso analogue.
The notation for amplitude measurements was accom-
plished according to a more generally applicable
method [16].
The limits of detection for the nitroso analogue were
experimentally determined using the concentrations 0.2
and 0.4 mg/ml for the first- and second-order derivative
spectra, respectively. Derivative spectra were recorded
in the wavelength range 450–250 nm, for three sample
solutions of each concentration, and limits of detection
were obtained by measuring the corresponding average
1
for amplitude D285 of the standard nitroso analogue
solution and the binary mixture is significant (Fig. 2(a),
curves 1 and 3). Determination of nisoldipine using a
first-order derivative spectrum was considered using the
1
2
1
values of amplitude D285 and D291 in comparison with
the noise signal (measured in u range 450–400 nm).
amplitude D386, since there was no influence of its
nitroso analogue (Fig. 2). A proposed assay for nisol-

V. Marinko6ic et al. / Il Farmaco 55 (2000) 128–133
131
In order to determine a lower content of the nitroso
analogue in the presence of nisoldipine, transformation
to the second-order derivative spectra was accom-
plished. In the second-order derivative spectrum of the
2
nitroso analogue, the amplitude D291 is entirely inde-
pendent of any nisoldipine present, confirming that this
derivative order is sufficient to deconvolute the overlap-
ping spectra of these compounds (Fig. 3). In the wave-
length range 275–320 nm the second-order derivative
spectrum of nisoldipine, at a higher concentration (20
mg/ml) than the one used for the first-derivative assay,
is actually zero. This was established by analyzing the
Fig. 3. Second-order derivative UV spectra of: nisoldipine (20 mg/ml;
curve 2); nitroso analogue (20 mg/ml; curve 1) and their binary
mixture of the same concentrations (curve 3).
2
1
amplitude D291 of the binary mixture with the corre-
dipine using the amplitude D386, in comparison with
2
sponding amplitude D291 of the standard nitroso ana-
the literature data [12] concerning first-order derivative
UV spectrophotometry for nifedipine determination us-
ing 214 nm as detection wavelength, offers a more
suitable wavelength for determination, as well as a
lower concentration range compared with the obtained
range for nifedipine of 5–45 mg/ml.
The least-squares regression equations for the first-
order derivative spectra obtained for nisoldipine and its
nitroso derivative in the concentration ranges 1–10 and
0.2–5 mg/ml, respectively, with the corresponding val-
ues for correlation coefficients are:
logue solution, since the same value is obtained (Fig. 3,
2
curves 3 and 1, respectively). The amplitude D291 cor-
responds to the peak of the long-wavelength satellite
with respect to the derivative baseline zero. Since satel-
lites in second- and also in fourth-derivative spectra are
rather smaller than the actual derivative peak itself,
some sensitivity may be lost, but the greater displace-
ment of a satellite away from the centroid peak may
fortuitously place it in a spectral zone clear of overlap-
ping interferences.
The amplitude of the centroid peak at 274 nm could
not be used, since as can be seen from Fig. 3 (curves 1
and 3), this amplitude is in a spectral zone of nisoldip-
ine overlapping interference.
for nisoldipine y=0.021× −0.0013; r=0.9993
for nitroso analogue y=0.1399× +0.0009; r=0.9999
Using a nitroso analogue concentration of 0.2 mg/ml,
the experimentally obtained value for the limit of detec-
tion was 0.05 mg/ml, defined as the concentration giving
an amplitude signal that is three times higher than the
noise signal, while a quantification limit of 0.15 mg/ml
was considered as the concentration that is three times
the limit of detection.
The least-squares regression equation for nitroso
analogue determination, in the second-order derivative
assay at 291 nm, in the concentration range 0.4–20
mg/ml, with the corresponding value for the correlation
coefficient is y=0.016× +0.0004; r=0.9998. The re-
2
peatability of the proposed method using D291 was
evaluated at a nitroso analogue concentration of 20
mg/ml, and the obtained RSD was 0.65% (n=6).
Using a nitroso analogue concentration of 0.4 mg/ml,
the experimentally obtained value for the limit of detec-
tion was 0.1 mg/ml, defined as the concentration giving
an amplitude signal that is three times higher than the
noise signal, while a quantification limit of 0.3 mg/ml
was considered as the concentration that is three times
the limit of detection.
The repeatability of the proposed method was evalu-
ated for concentrations of 10 and 5 mg/ml of nisoldipine
and nitroso analogue, respectively, and the obtained
values of relative standard deviations (RSD) were 0.44
and 0.62% (n=6).
The effect of high concentrations of nisoldipine on
the determination of the nitroso analogue was evalu-
ated by determining the percentage recovery of the
nitroso analogue in binary mixtures. The solution con-
taining a constant nisoldipine concentration of 5 mg/ml,
with no detectable amount of its nitroso analogue, was
spiked with an aliquot at two concentrations of 0.25
and 0.5 mg/ml of the nitroso analogue. The percentage
Stock solutions containing a fixed nisoldipine con-
centration of 0.1 mg/ml, with no detectable amount of
its nitroso analogue, were diluted to a working concen-
tration of 20 mg/ml and were spiked with an aliquot of
a nitroso analogue solution at two concentrations of 0.4
and 1 mg/ml (equivalent to impurity levels of 2 and 5%,
respectively). The percentage recoveries for the nitroso
1
recoveries achieved using the amplitude D285 were 98.7
and 100.1% (n=5). Considering the recovery values,
the minimal detectable amount of nitroso analogue in
the presence of nisoldipine at a concentration of 5
mg/ml was 0.25 mg/ml (equivalent to an impurity level
of 5%). Using the first-order derivative spectrum, the
determination of the nitroso analogue was not feasible
at an impurity level lower than 5%.
2
analogue using the amplitude D291 were 100.98 and
99.79%, respectively (n=5). Considering the obtained
recovery values, the minimal detectable amount of ni-
troso analogue in the presence of nisoldipine was 0.4
mg/ml (equivalent to an impurity level of 2%).

132
V. Marinko6ic et al. / Il Farmaco 55 (2000) 128–133
Table 1
The degradation analysis of nisoldipine raw material and commercial forms of nisoldipine
Sample
Days
Nisoldipine raw material % degradation a Nisoldin® tablet (10 mg) % degradation a Nisoldin® tablet (5mg) % degradation a
First-order
Second-order
First-order
Second-order
First-order
Second-order
5
9.80
20.00
25.59
38.50
42.50
49.90
9.90
20.05
26.70
37.75
42.10
48.89
10
15
20
25
30
2.10
2.70
3.60
4.50
5.80
2.10
2.60
3.50
4.00
4.50
6.00
5.00
a % degradation defined as nitroso analogue content expressed in %. Three replicates of each sample determination with average value of RSD
(%) up to 1.1%.
3.2. Photostability studies
first-order and second-order UV-derivative assay were
satisfactory for routine analysis of nisoldipine degrada-
tion. Transformation of the broad absorption spectrum
of nisoldipine to the first-order derivative spectrum
offers more sensitive determination of nisoldipine using
1D386, whereby the wavelength of the amplitude is
better defined in comparison with the wavelength of the
absorption maximum in zero-order spectra, which is
substantial for the analysis concerning dissolution tests.
The first-order derivative assay of the nitroso ana-
logue has the advantage for the stability analysis of
nisoldipine raw material, as well as for the investiga-
tions of nisoldipine stability in organic solvents, due to
the relatively fast degradation process. The first-order
derivative assay for the nitroso analogue has a limita-
tion with the parent-compound concentration (up to
5% impurity level). Using the second-order derivative
spectrum (2D291) the determination limit of the nitroso
analogue in nisoldipine was considerably lower (2%
impurity level). This derivative order has an advantage
over the first order for the analysis concerning the
stability of dosage forms.
The first- and second-order derivative assay was ap-
plied to the analysis of commercial dosage forms of
nisoldipine (Nisoldin® tablets) in comparison with
nisoldipine raw material, before and after irradiation by
daylight. The obtained results are presented in Table 1.
Both the first- and second-order derivative spec-
trophotometric methods can be used for nitroso ana-
logue determination in nisoldipine raw material, since
its content is already approximately 10% after 5 days of
irradiation by daylight. Only the second-order deriva-
tive assay can be utilized for Nisoldin® tablets for the
period between 5 and 30 days. The first-order derivative
assay is feasible for analysis of dosage forms only after
30 days, when the nitroso analogue content was found
to be 5% or higher than 5%.
Regression and correlation analysis was applied to
the dependence of the nitroso analogue content (ex-
pressed in %) on time (days) of exposure to daylight.
On the basis of the linear dependence (correlation
coefficients r\0.99) of the increase of nitroso analogue
content on exposure time to daylight of nisoldipine raw
material, as well of Nisoldin® tablets, the calculated
maximal degradation rate in nisoldipine raw material
was found to be 1.6% per day, while significantly lower
and related values were obtained of 0.19% per day and
0.15% per day for 10 and 5 mg Nisoldin® tablets,
respectively.
Daylight is an important factor in storage of the raw
material, standard substance, as well as the dosage
forms of nisoldipine. The film of the tablets protected
nisoldipine from photodegradation, and the obtained
results established that the degradation rate of the film
tablets was ten times lower than that of the nisoldipine
raw material.
2
Since the whole amplitude D291,274 has not been used
in this assay, but only the long-wavelength satellite
2
amplitude D291, the value of the minimal detectable
amount of nitroso analogue (2%) could not be lower,
but it is sufficient to follow degradation kinetic where
fast and significant changes are obtained.
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