Microchemical Journal 132 (2017) 365370

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Microchemical Journal

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Alternative method for chromium determination in pharmaceutical

drugs by HR-CS GF AAS and direct analysis of solid samples
Eliana G. Barrera, Dbora Bazanella, Paula W. Castro, Wiliam Boschetti, Maria G.R. Vale, Morgana B. Dessuy
Universidade Federal do Rio Grande do Sul, Bento Gonalves, 9500, 91501970 Porto Alegre, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: High-resolution continuum source graphite furnace atomic absorption spectrometry (HR-CS GF AAS) was used to
Received 21 November 2016 develop an analytical method for chromium determination in pharmaceutical drugs through direct analysis of
Received in revised form 15 February 2017 solid samples. The limit of detection and quantication were, respectively, 2.9 g kg1 and 9.7 g kg1 and the
Accepted 16 February 2017
characteristic mass was 2.0 pg. Eighteen pharmaceutical drugs and three excipients were analyzed. The encapsu-
Available online 20 February 2017
lated samples were opened and only its powder content was analyzed; the tablet samples were grinded before
Keywords:
the analysis. The results obtained from the direct analysis of the solid samples were in agreement with those
Pharmaceutical drugs found after total digestion of samples using a closed-vessel microwave oven device, with a condence level of
Direct analysis 95%. The Cr concentration obtained for the different capsules and tablets investigated varied between 0.05 and
HR-CS GF AAS 1.92 mg kg1. The proposed method is fast, reliable and simple for routine pharmaceutical analysis.
Chromium 2017 Elsevier B.V. All rights reserved.

1. Introduction determine the potentially toxic elements concentration, as the solid

In the pharmaceutical industries, a variety of metals and nonmetals
are used in the manufacture of drugs, or even used as the active phar-
maceutical ingredient (API) in medicine products [1]. Thus, it is com-
mon to nd metallic impurities on the nal products originated from
different sources, as raw materials (plants, animal proteins, etc.),
metal catalysts or metal reagents used during synthesis, excipients (sta-
bilizers, llers, release agents, avors, color), manufacturing equipment
and piping, bulk packaging, the environment, cleaning solvents, etc. [2].
Considering the elements generally found in medicine formulations,
chromium can be associated with potential health risks as chromosomal
aberration, mutations and carcinogenicity, just to mention a few [3].
Taking into account the increasing consumption of pharmaceutical
drugs by humans, it is important to highlight that the quality control
of these medicines is vital to guarantee the nal consumers safety [1,
46]. The permissible levels of potentially toxic elements in pharmaceu-
ticals are usually dened by the regulatory agencies. For example, the
permissible limit of chromium impurities in drugs established from Bra-
zilian Pharmacopeia [7] via oral use is 25 g g1, while the United States
(USP) [8] and European Pharmacopeia (EP) [9] have settled a value of
1100 g g1, considering maximum daily dose of 10 g of drug products.
Brazilian Pharmacopeia [7] indicates two methods for elements deter-
mination: the solid particles formation and the atomic spectrometry,
which are also indicated by the USP [8] and the EP [9]. In this context,
the atomic spectrometry techniques play an important role in order to
Corresponding author.
E-mail address: mbdessuy@ufrgs.br (M.B. Dessuy).
particles formation test provides only semi-quantitative results.
Therefore, analytical methods that provide trustworthy results
through a fast and simple way are essential. Atomic absorption spec-
trometry (AAS) technique is recommended by Brazilian Pharmacopeia
for As, Cd, Cr, Cu Hg, Ir, Mn, Ni, Os, Pb, Pd, Pt, Rh, Ru and V determination
in pharmaceutical drugs [7]. Among AAS techniques, graphite furnace
(GF AAS) shows higher sensitivity when compared to ame AAS [10,
11]. Inductively coupled plasma-optical emission spectroscopy (ICP
OES) [2,12], inductively coupled plasma-mass spectrometry (ICP-MS)
[13,14], electrothermal vaporization inductively coupled plasma optical
emission spectrometry (ETV-ICP OES) [15] and laser ablation inductive-
ly coupled plasma-mass spectrometry (LA-ICP-MS) [16] also can be
used in the analysis of pharmaceutical compounds. However, most of
these techniques require sample pretreatments which, besides of
being time consumable, can lead to sample losses or contamination
and sensitivity decrease, mainly due to the use of different reagents
and sample dilutions [1015,17].
In this context, the direct analysis of solid samples (SS) by graphite
furnace atomic absorption spectrometry (SS-GF AAS) is an effective
tool to overcome the issues found on the sample pretreatments [18,
19]. Thus, the benets and interests of SS-GF AAS on commercial cap-
sules and tablets analysis arise from its simple manipulation and the
possibility to be employed on industrial routine protocol. More recently,
with the advent of the high-resolution continuum source AAS (HR-CS
AAS), the direct analysis of solid samples by graphite furnace (HR-CS
SS-GF AAS) became more consolidated and feasible [2022].
The use of the SS-GF AAS for Cr determination is described by several
authors which analyzed different matrices as medicinal plants [23],
crude oil [24] tannin samples [25], biomass and its ashes [26], sunscreen

http://dx.doi.org/10.1016/j.microc.2017.02.020
0026-265X/ 2017 Elsevier B.V. All rights reserved.
366 E.G. Barrera et al. / Microchemical Journal 132 (2017) 365370

samples [27], soil samples [28] and high purity polyimide samples [29].
It is noteworthy that these authors do not report the use of chemical
modiers for Cr determination. On the other hand, but still considering
the employment of the SS-GF AAS, there are works that describe the use
of chemical modiers, mainly to overcome matrix interferences over
the Cr analytical signal. The most common chemical modier employed
for Cr determination in different matrices, as soil certied reference ma-
terials [30], fertilizer samples [31] and vegetable oil and biodiesel sam-
ples [32], is a Mg(NO3)2 solution.
All these works report that the direct analysis of solid sample is an
efcient analytical tool, due to the elimination of many steps involved
in the sample preparation, reducing the time of analysis and the risk
of contamination and it, also, avoids the sample dilution, increasing
the sensitivity of the method. Moreover, the combination of direct anal-
ysis of solid samples with the HR-CS AAS technique provides much
more information about the spectral environmental around the analyt-
ical line, which facilitates the method development and the detection of
spectral interferences and its correction. Besides these advantages, this
technique has not been explored yet in order to perform the analysis
of commercial pharmaceutical drugs capsules and tablets. Fig. 1. Pyrolysis curves for Cr evaluating () a pharmaceutical drug (PD1) with the Aint
values normalized to a sample mass of 0.5 mg and () a Cr (100 pg) aqueous standard
The main goal of this work has been the development of a simple,
solution. Tatom = 2600 C.
fast and reliable analytical method for chromium determination in
pharmaceutical drugs commercialized as capsules and/or tablets, as
well as on excipients by HR-CS GF AAS using direct analysis of solid injected manually onto the platform using a micropipette. It was carried
samples. out 5 measurements of each sample and standard solution.
A microwave reaction system, Multiwave PRO, (Anton Paar, Graz,
Austria) was used for the acid digestion of the samples in order to verify
2. Experimental the accuracy of the developed method.

2.1. Instrumentation
2.2. Reagent and solutions
All measurements were performed in a high-resolution continuum
source graphite furnace atomic absorption spectrometer (HR-CS GF Analytical grade reagents were used exclusively. Ultra-pure water
AAS), contrAA 700 model (Analytik Jena, Jena, Germany). This instru- with a specic resistivity of 18 M cm1 from a Milli-Q water purica-
ment is equipped with a xenon short-arc lamp with a nominal power tion system (Millipore, Bedford, MA, USA) was used in the preparation
of 300 W operating in a hot-spot mode, a high-resolution double mono- of standards and digested solutions. The nitric acid (Merck, Darmstadt,
chromator and a linear charge coupled device (CCD) array detector with Germany) used for the preparation of standards and digestions was pu-
588 pixels. The analytical line at 357.868 nm was used for the measure- ried by sub-boiling distillation in a quartz apparatus (Krner
ments and the integrated absorbance (Aint) of center pixel (CP) and the Analysentechnik, Rosenheim, Germany). Aqueous standard solutions
two adjacent pixels, i.e. CP 1, was summed and used for signal evalu- were prepared by appropriate dilutions of a stock solution of
ation. Argon with purity of 99.996% (White Martins, So Paulo, Brazil) 1000 mg L1 of Cr (Specsol, So Paulo, Brazil) with 0.014 mol L1 nitric
was used as purge gas. The argon ow rate was kept in 2.0 L min1 dur- acid.
ing all stages, except in the atomization, when it was stopped. The opti-
mized graphite furnace temperature program for Cr determination is
shown in Table 1.
Transversely heated graphite tubes without a dosing hole (Analytik
Jena, Part No. 407152.316) and solid sampling graphite platform
(Analytik Jena, Part No. 407152.023), both coated with pyrolytic
graphite were used in all experiments. An M2P microbalance (Sartorius,
Gttingen, Germany - accuracy 0.001 mg) was used for weighing the
pulverized samples directly onto the SS platforms. A pre-adjusted pair
of tweezers, which is part of the SSA 6 manual solid sampling accessory
(Analytik Jena, Jena, Germany), was used to transfer the SS platforms to
the atomizer. The aqueous standards and digested solutions were

Table 1
Graphite furnace temperature program for Cr determination in commercial pharmaceuti-
cal drugs by HR-CS SS-GF AAS.

Stage Temperature/C Ramp/C s1 Hold time/s

Drying 1 90 30 20
Drying 2 120 10 20
Pyrolysis 1200 500 30
Atomizationa 2600 3000 6
Cleaning 2650 1000 5
Fig. 2. Atomization curves for Cr evaluating () a pharmaceutical drug (PD1) with the Aint
a
Argon ow rate was 2.0 L min1 in all stages, except during the atomization, when it values normalized to a sample mass of 0.5 mg and () a Cr (100 pg) aqueous standard
was interrupted. solution. Tpyr = 1200 C.
 E.G. Barrera et al. / Microchemical Journal 132 (2017) 365370
2.3. Sample preparation procedures
2.3.1. Solid sample pretreatment
Eighteen pharmaceutical drugs and three excipients were obtained
from local drugstores in Porto Alegre (Rio Grande do Sul, Brazil). The en-
capsulated samples were opened and its powder content was analyzed
without any treatment. The tablet samples (PD11, PD12, PD13 and
PD17) containing an external coating layer were grinded using an agate
mortar and sieved through a 180 m mesh. Sample masses between 0.2
and 7.5 mg of the pharmaceutical drugs or excipients were weighted
onto the SS platforms and introduced into the graphite furnace for mea-
surement. As it is not possible to weight always the same sample mass,
they were transmitted to the instrument's computer to calculate the nor-
malized Aint (calculated for 0.5 mg of sample) after each measurement.
2.3.2. Samples digestion and recovery tests
Four samples were submitted to an acid digestion procedure in
order to verify the trueness of the developed method, using a
Fig. 3. Absorbance signal at (\
\) 2500 C and () 2600 C for chromium in (a) aqueous standard solution (100 pg) and (b) pharmaceutical drug (PD1).
367
microwave system equipped with PTFE-TFM closed vessels of 50 mL.
Approximately, 0.15 g of each sample was transferred to the vessels
with further addition of 3 mL of concentrated nitric acid and 1 mL of
concentrated hydrochloric acid. The samples were submitted to the fol-
lowing heating program, performed in two steps (temperature in C/
ramp in min/hold in min): (i) 130/30/5; (ii) 180/20/5. After cooling,
the vessels content were transferred to 20 mL volumetric asks and
the nal volume was completed with ultrapure water. Recovery tests
were carried out using these four digested samples. In this case, ade-
quate aliquots of chromium standard solution were added to the sam-
ples before they were submitted to the digestion procedure.
3. Results and discussion
3.1. Temperature program
As chromium is known as thermally stable element, the method op-
timization and the analyses of pharmaceutical samples were carried out
368 E.G. Barrera et al. / Microchemical Journal 132 (2017) 365370
without a chemical modier. The heating program was optimized using
10 L of an aqueous standard solution of Cr 10 g L 1, which corre-
sponds to 100 pg of analyte, and a commercial sample of pharmaceuti-
cal drug (PD1). Initially, pyrolysis temperatures (Tpyr) between 300 C
and 2000 C were evaluated maintaining the atomization temperature
at 2600 C. Fig. 1 shows that the Cr Aint values for the aqueous standard
solution and for the investigated sample are stable up to 1500 C and for
higher temperatures the Aint values decreases due to Cr losses. In other
words, it indicates that standard solution and sample presents similar
thermal behavior. In order to guarantee the complete matrix elimina-
tion and to preserve the graphite furnace life time, the temperature of
1200 C was chosen and it was used in all further experiments. More-
over at 1200 C a better precision, which can be observed as the relative
standard deviation (RSD), was obtained for the samples, RSD = 4.2%.
Considering that Cr is known as a nonvolatile element [10], atomiza-
tion temperatures (Tatom) between 2300 and 2600 C were evaluated. It
is possible to observe in Fig. 2 that Cr Aint values for the PD1 sample pre-
sented a slightly increase with the temperature rising. On the other
hand, the Aint values for Cr standard solution remained stable up to
2500 C, with a small decrease at 2600 C, which may be attributed to
the Cr peak shape (Fig. 3a), as at 2500 C the analytical signal was
Fig. 4. Time-resolved absorbance spectra of Cr for (a) PD7 (m = 0.719 mg, Aint = 0.1167 s)
and (b) PD17 (m = 0.108 mg, Aint = 0.4247 s) pharmaceutical drugs samples. Tpyr = 1200 C
and Tatom = 2600 C.
broader and more tailing than at 2600 C, i.e. the peak area was higher
at 2500 C than at 2600 C. However, as a more symmetrical peak was
obtained, at 2600 C, this temperature was preferable since a shorter in-
tegration time can be used, which can contribute to an improved signal
to noise ratio and, consequently, lower limits of detection (LOD) and
quantication (LOQ) values. Considering Cr atomization from sample,
a higher atomization temperature is more convenient also, since it re-
sults in a higher amount of analyte atomized (Fig. 3b).
Fig. 4 shows two time-resolved absorbance spectra obtained using
the optimized temperatures of 1200 and 2600 C evaluating two differ-
ent samples (PD7 and PD17). No spectral interferences and symmetric
peaks are observed. Therefore, the Tpyr and Tatom used in all further mea-
surements were 1200 and 2600 C, respectively. It is important to men-
tion that under these conditions the graphite furnace lifetime was
approximately 330 cycles. Furthermore, considering the absence of
spectral interferences during the samples analyses it is clear that the
pharmaceutical drugs can be directly analyzed even by a line source
spectrometer.
3.2. Study of inuence of sample mass
The direct analysis of solid samples can nd some difculties related
to inhomogeneity of samples, errors due to the use of different masses,
limited sample size and high RSD values [3335]. Hence, to check the in-
uence of the sample mass introduced onto the graphite furnace under
optimized conditions, the correlation of different masses of a pharma-
ceutical drug (PD1) sample and their respectively Cr Aint values were
evaluated. Samples masses between 0.20 and 7.5 mg were weighted
and an adequate correlation coefcient (0.9850) was obtained. Higher
amounts of samples were not investigated due to the platform capacity,
which was reasonably full when sample masses above 7.5 mg were
evaluated. This result indicates that the sample mass does not inuence
the analytical response, i.e., the Cr Aint.
3.3. Figures of merit
Calibration curves were established using a blank and calibration so-
lutions in the concentration range of 2.540 g L1 (25400 pg). Blank
measurements were carried out according to the zero mass response
principle [18] using the empty SS platform.
The LOD and LOQ are dened as three and ten times the standard de-
viation of ten measurements of the blank, respectively, both divided by
the slope of the calibration curve. The characteristic mass (m0) is de-
ned as the mass of the analyte corresponding to an integrated absor-
bance of 0.0044 s. The relative LOD and LOQ were calculated for
7.5 mg of sample, which corresponds to the maximum sample mass
that can be analyzed.
The analytical gures of merit obtained for Cr are shown in Table 2.
Wollein et al. [36] measured Cr in active pharmaceutical substances
with GF AAS using the Cr analytical line at 357.9 nm achieving a LOQ
of 0.05 g g1 for 400 mg of digested samples. Using the same wave-
length, De Paula et al. [37] determined Cr in pharmaceutical formula-
tions via GF AAS using a ultrasound-assisted extraction method and
obtained a LOQ of 200 ng g1, considering a sample mass of 25 mg.
Virgilio et al. [23], evaluating medicinal plants via HR-CS SS-GF AAS,
Table 2
Figures of merit for the determination of Cr in pharmaceutical drugs using HR-CS SS-GF
AAS. Tpyr: 1200 C and Tatom: 2600 C.
Parameters Cr (357.868 nm)
Linear regression equation A = 0.0021 m (pg) + 0.0044
Correlation coefcient 0.9980
LOD (pg/ng g1) 2.9/0.39a
LOQ (pg/ng g1) 9.7/1.3a
mo 2.0 pg
a
LOD and LOQ calculated for the maximum sample mass used: 7.5 mg.
 E.G. Barrera et al. / Microchemical Journal 132 (2017) 365370 369

determined the gures of merit for Cr using aqueous standard solutions
and obtained LOQ of 11 ng g1 and characteristic mass (m0) of 4.8 pg.
Zmozinski et al. [25] determined Cr in tannin samples using HR-CS SS-
GF AAS and obtained a m0 of 2.2 pg and LOQ of 57 ng g1, calculated
for 0.25 mg of sample. In other words, the gures of merit obtained in
this work (m0 of 2.9 pg and LOQ of 0.39 ng g1, calculated for a sample
mass of 7.5 mg) are in agreement or even better with those reported in
literature. Moreover, LOD and LOQ are comfortable lower than the max-
imum Cr allowed by Brazilian (25 g g 1), US and European
(1100 g g1) pharmacopeia.
3.4. Recovery tests and analytical results
4. Conclusion
In this work it was developed an accurate, fast and reliable analytical
method for the determination of Cr in pharmaceutical drugs and excip-
ients by HR-CS GF AAS and direct analysis of solid samples. It avoided
the intensive manipulation of the samples, reducing time and cost of
the analysis besides the risk of sample contamination. The developed
method allows the use of aqueous standards solutions for calibration,
conrming that this method is simple and suitable for routine applica-
tions. All commercial analyzed samples showed Cr content much
lower than values established by current Brazilian, US and European
Pharmacopeias.

Acknowledgements
To obtain a most reliable result, pharmaceutical drugs containing an
external coating (PD11, PD12, PD13 and PD17) were grinded and
The authors are grateful to the Conselho Nacional de
sieved, as preliminary studies without sieving showed high values of
Desenvolvimento Cientco e Tecnolgico (CNPq), and Coordenao
RSD (N 30%). After this procedure, it was possible to achieve a better
de Aperfeioamento de Pessoal de Nvel Superior (CAPES) for their -
sample homogeneity, leading to more satisfactory RSD values (b13%).
nancial support. M.G.R.V. has scholarship from CNPq (grant no.
Due to the lack of certied reference material for pharmaceutical
305679/2015-5) and W.B. (grant no. 1533/2013) and E.G.B. (grant no.
drugs, the trueness of the proposed method was evaluated by compar-
23038007479201144) from CAPES.
ing the results of the SS analysis with those obtained by analyzing the
samples after an acid digestion. In this context, four drugs were ana-
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