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Talanta 166 (2017) 223227

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A feasible method for indirect quantication of L-T4 in drugs by iodine MARK


Marcia Foster Mesko , Alessandra Cortes Teotonio, Dirce Taina Teixeira Oliveira, Diogo La Rosa
Novo, Vanize Caldeira Costa
Centro de Cincias Qumicas, Farmacuticas e de Alimentos, Universidade Federal de Pelotas, Campus Capo do Leo, 96160 000, Capo do Leo, Brazil


Keywords: In this work, a method combining microwave-induced combustion (MIC) for sample preparation of commercial
Sodium levothyroxine determination levothyroxine sodium (L-T4) drugs (L-T4: 25200 g/tablet), and potentiometry with ion selective electrode
Iodine determination (ISE) for iodine determination and subsequent indirect quantication of L-T4 was proposed. The type and
Drug analysis concentration of the absorbing solution were evaluated to select the most suitable conditions for this study.
Microwave-induced combustion
Using the MIC method, it was possible to use solutions as diluted as 150 mmol L1 (NH4)2CO3 (for samples
Sample preparation
containing 25200 g of L-T4/tablet) for I absorption. In these conditions, recoveries for L-T4 were between
Ion selective electrode
99% and 101%, and relative standard deviations were lower than 10%. The limit of detection for L-T4 was
11.2 g/tablet, which is almost two times lower than the minimum concentration of L-T4 in commercially
available drugs. Thus, the MIC was suitable for the digestion of several L-T4 drugs for subsequent I
determination by ISE and indirect quantication of L-T4. Furthermore, the proposed method presents high
throughput with low reagent consumption and consequently lower waste generation, making it suitable for
routine determination of L-T4 in drugs. From the obtained results, it was possible to observe that one of the
analyzed samples is not in agreement with the limits established by the United States Pharmacopeia, indicating
the importance of the drug quality control. The United States Pharmacopeia establishes that each tablet must
contain between 90% and 110% of the amount of active substance declared by the manufacturer.

1. Introduction Methods for analysis of the activity pharmaceutical ingredient and/

or tablets containing L-T4 are described in ocial compendiums. These
The thyroxine (T4) and triiodothyronine (T3) hormones secreted methods usually involve the use of the high-performance liquid
from the thyroid gland present an important biological role in the chromatography (HPLC) for the determination of L-T4 [5,6], which
development of the central nervous system in infants, the skeletal presents as disadvantages the time consuming for analysis, interfer-
growth and for the normal function of multiple organ system in adults ences from matrix compounds, among others. Moreover, it is impor-
[1]. The deciency of these hormones in the organism causes tant to highlight that, in general, the interferences in L-T4 assay are
hypothyroidism, which is a disorder with numerous symptoms, such related to the matrix composition and solubility of the excipients, and it
as myxedema with struma and debility [2]. For the treatment of the can cause high variability in the results [7]. Another method involves a
hypothyroidism, pharmaceutical preparations containing the thyroid sample preparation using the Schniger ask that generally allows the
hormones are used. The levothyroxine sodium (L-T4) - a sodium salt of digestion of a small sample mass and low throughput [8,9]. In this
levo-isomer of T4 - is the most common drug prescribed to treat this method, the determination of L-T4 is performed indirectly by the
disease [1,2]. The L-T4 has a narrow therapeutic index; thus, doses titration of the iodine present in the sample. Nevertheless, the titration
outside of the therapeutic window may cause the side eects of is a technique with low sensibility and contributes to the obtainment of
hyperthyroidism or hypothyroidism in patients, such as adverse cardiac high limits of detection (LODs), making dicult the determination of
and/or metabolic eects [3,4]. In this way, the determination of L-T4 in L-T4 in low concentrations [10].
commercially available drugs using a sensitive method is important to In this context, it is also important to mention that there are
ensure that the dose present in the medicament corresponds to the relatively few studies in literature reporting methods for the determi-
informed. nation of L-T4 in drugs [13,1119]. In most of the studies, the

Corresponding author.
E-mail address: marcia.mesko@pq.cnpq.br (M.F. Mesko).

Received 12 December 2016; Received in revised form 11 January 2017; Accepted 12 January 2017
Available online 13 January 2017
0039-9140/ 2017 Elsevier B.V. All rights reserved.
M.F. Mesko et al. Talanta 166 (2017) 223227

commercial L-T4 drugs were dissolved in a suitable medium and Table 1

analyzed by HPLC [13,12]. However, depending on the concentration Operational parameters for iodine determination by IC.
of L-T4 in pharmaceutical preparations, the sensitivity of HPLC with
Parameter Operation conditions
ultraviolet detection can be not suitable, especially at low concentra-
tions, for detection and quantication of subtle but signicant dier- Mobile phase 3.2 mmol L1 Na2CO3/1.0 mmol L1 NaHCO3 (pH 10.5)
ences in L-T4 concentrations [3,4]. Other methods used for L-T4 Flow rate 0.7 mL min1
Sample loop 20 L
determination in commercial drugs involve the use of immunoassays,
Column Anion-exchange, Metrosep A Supp 5 (polyvinylalcohol with
capillary electrophoresis, and electroanalytical and spectrometric tech- quaternary ammonium groups, 250 mm x4 mm i.d.)
niques [13,1519]. In spite of some electroanalytical techniques had Guard column Metrosep A Supp 4/5 Guard (polyvinylalcohol with quaternary
been used for the determination of L-T4 and the potentiometry with ion ammonium groups, 5 mm x4 mm i.d.)
selective electrode (ISE) to be a simple and an inexpensive device, it is Suppressor Chemical type
Detection Conductivity
important to highlight that this technique still was not evaluated for the
determination of I and the indirect quantication of L-T4 in drugs.
Considering the advantages of the potentiometry with ISE, such as 2. Experimental section
relatively good sensitivity and selectivity and fast response time, it is
possible to consider the use of this technique as an alternative for the 2.1. Instrumentation
indirect quantication of L-T4 in routine analyses. However, the
potentiometry with ISE is extremely prone to interferences caused by The MIC method was performed in a microwave oven (Multiwave
ions with hydration energy and ionic radius similar to the analyte or 3000 microwave sample preparation system, Anton Paar, Austria)
that form complexes with the specie to be determined [20,21]. Thus, it equipped with eight high-pressure quartz vessels with an internal
is necessary to use an appropriate sample preparation method to volume of 80 mL (maximum pressure and temperature of 80 bar and
ensure the release of I from the sample matrix and the accuracy of L-T4 280 C, respectively). Quartz holders were inserted inside the vessels as
determination by potentiometry with ISE in commercial drugs. In this support for the samples during the combustion process.
sense, considering the major organic composition of L-T4 drugs and the Iodine determination was carried out using a potentiometer (HI
unsuitability of wet digestion for the subsequent determination of I, 3221 pH/ORP/ISE meter, HANNA Instruments, USA) equipped with
combustion methods can be considered as an alternative for the an ISE of iodide (HI 4111, HANNA Instruments, USA). A hot plate
digestion of drug samples and the subsequent determination of I by with agitation (RH Basic, IKA, USA) was used for the homogenization
ISE for the indirect quantication of L-T4 [22]. of the samples during I determination by ISE. Additionally, for
The microwave-induced combustion (MIC) method allows the comparison of results, the determination of I was performed using an
conversion of an organic matrix to the respective oxidation products, ion chromatograph (IC 2.861.0020, Metrohm, Switzerland), and the
and the high temperature reached during combustion enables quanti- operating conditions are shown in Table 1.
tative halogen release from the sample [8,23]. In the MIC, it is possible
to digest sample masses higher than those commonly digested using
Schniger ask (sample preparation method recommended in ocial 2.2. Reagents and samples
compendium for indirect determination of L-T4) due to the possibility
of pressurization of the system with oxygen. Moreover, the MIC has a All solutions were prepared using ultrapure water (18 M cm)
high sample throughput and, as the Schniger ask, allows the use of obtained from a purication system (MegaUp, MegaPurity, South
reagents suitable to the analytes and the determination technique [8]. Korea), and the reagents used were of analytical grade or higher purity.
For digestion of organic samples by the MIC, samples are usually Water and ammonium carbonate solutions (50150 mol L1) were
prepared as pellets and positioned on a quartz holder. The combustion used as absorbing solution in the MIC. Solutions of (NH4)2CO3 and a
occurs in a closed quartz vessel pressurized with oxygen, and the solution of ammonium nitrate (6 mol L1), used as the igniter of the
ignition step is performed using microwave radiation and an ammo- combustion, were prepared by the dissolution of solid reagents (Merck,
nium nitrate solution. After combustion, the analytes are absorbed in a Germany) in water.
suitable solution, which can be compatible with the analytes and the Small discs (12 mg, 15 mm of diameter) of lter paper (0.5% ash
determination technique [22,24]. content, Qualy, J Prolab, Brazil) were used as a combustion aid, and
Recently, the MIC has been successfully applied to the digestion of polyethylene (PE) lms were used to wrap the samples for digestion by
organic samples for further determination of halogens, such as foods, the MIC. Before combustion, the discs of lter paper and PE lms were
polymers, and drugs [23,2531]. In addition, the MIC is recommended cleaned by immersion in 10% (v v1) HNO3 (Vetec, Brazil) for 20 min
in Brazilian Pharmacopeia for digestion of organic samples that may in an ultrasonic bath (USC-1800 A, Unique, 40 kHz, 155 W, Brazil),
not be eciently digested even using wet digestion in closed system, subsequently rinsed with ethanol (Synth, Brazil) and ultrapure water,
and it is reported as a suitable sample preparation method for and dried in a class-100 laminar bench (CSLH-12, Veco, Brazil).
subsequent halogens determination in drugs. However, this method Oxygen (99.6%, White Martins, Brazil) was used for the vessels
still was not recommended for the digestion of L-T4 drugs and the pressurization for the MIC method.
subsequent determination of I [32]. Vessels and holders were cleaned with 6 mL of 14.4 mol L1 HNO3
Thus, considering the importance of the determination of L-T4 in (Vetec, Brazil) using a microwave heating program set at 1000 W for
commercial drugs, in the present work, a method using the MIC is 10 min and 0 W for 20 min (cooling step). After, this procedure was
proposed for drug digestion and the subsequent determination of I by repeated using 6 mL of water instead of HNO3.
ISE for the indirect quantication of L-T4. For both, a systematic study The standard solutions used for the determination of I by IC and
was performed paying special attention to the sample preparation step. ISE were prepared by the dilution of a stock standard solution
The accuracy of the proposed method was evaluated by the comparison (0.1 mol L1, HI 4011, HANNA Instruments, USA) in a suitable
of the obtained results by ISE to those determined in digests by IC and medium. Moreover, for I determination by ISE, 2 mL of ionic strength
by recovery tests using an L-T4 standard solution. adjuster (HI 4000-00, HANNA Instruments, USA) were used per
100 mL of sample or standard solution. The mobile phase
(3.2 mmol L1 sodium carbonate and 1.0 mmol L1 sodium bicarbo-
nate) used for the determination of I by IC was prepared by the
dissolution of the respective salts (Merck, Germany) in water.

M.F. Mesko et al. Talanta 166 (2017) 223227

Sodium levothyroxine (high purity L-T4 from Pharmanostra was possible to digest up to 800 mg of the L-T4 drug.
Company, Brazil) was diluted in 500 mmol L1 NH4OH to obtain the However, taking into account that the samples contained a sig-
reference solution (L-T4: 1875 mg L1) used for L-T4 recovery tests. nicant iodine concentration and the sample mass commonly used in
The solubilization of L-T4 in an alkaline solution was necessary, the MIC method [8,34], the subsequent studies were performed using
because it has low solubility in water. 400 mg of sample. In this context, it is important to mention that this
Commercial L-T4 drugs of the same brand (labeled as brand A) sample mass was also selected to avoid excessive dilutions, considering
and containing 25, 50, 100, 150 or 200 g of L-T4 per tablet (produced the content of I in some therapeutic doses, and for safety aspects.
in Germany or Mexico) were purchased in local drugstores. Drugs However, it is important to mention that depending on I content in
containing 100 or 200 g of L-T4 per tablet were chosen for initial drug higher sample mass can be used.
experiments because these samples had an intermediary and high Therefore, 400 mg of the L-T4 drug were digest by the MIC using a
concentration of L-T4, respectively, when compared to the other drugs. PE lm for sample wrapping and a pressure of O2 of 20 bar. Moreover,
After, optimized conditions were used for digestion of the samples in these conditions, the maximum pressure achieved was lower than
containing 25, 50 or 150 of L-T4 per tablet. 30 bar, which corresponds only about 35% of the maximum operating
In addition, the proposed method was applied to L-T4 determina- pressure of the microwave system (80 bar).
tion in drug samples of two other brands (produced in Germany,
Mexico or Puerto Rico, and labeled as brands B and C) containing
3.2. Inuence of absorbing solution on I recoveries after the digestion
low (25 g/tablet) or high (200 g/tablet) concentrations of L-T4.
of commercial L-T4 drugs by the MIC
Before digestion by the MIC, the samples were ground using a
porcelain mortar and pestle to homogenize the samples and reduce
To select the most suitable solution for the absorption of I after the
the particle size, and dried at 60 C for 3 h.
digestion of drug samples by the MIC, water or (NH4)2CO3 solutions
(50150 mmol L1) were evaluated. These solutions were selected
2.3. Sample preparation by MIC
according to previous works that aimed the determination of halogens
in a variety of matrices [29,3436]. Experiments were carried out by
Commercial L-T4 drugs (400 mg) were weighed and wrapped with a
adding of 100 L of the L-T4 reference solution (1875 mg L1) on drug
PE lm (88 cm). After closing the PE lm as a small wrap, the lm
samples containing 100 or 200 g of L-T4/tablet prior to digestion by
was sealed by heating, and its excess was removed (PE lm mass used
the MIC. The drugs containing 100 or 200 g of L-T4/tablet were
in the MIC was approximately 30 mg). The wrap of PE containing the
selected for initial studies, because these samples had an intermediary
sample was placed with a small disc of lter paper moistened with an
and high concentration of L-T4, respectively, contributing to the
NH4NO3 solution (50 L of 6 mol L1) on the base of a quartz holder.
evaluation of the proposed method in a broad manner. Results are
The quartz holder was then introduced into the quartz vessel contain-
shown in Fig. 1.
ing 6 mL of absorbing solution (water or 50, 100 or 150 mmol L1
As shown in Fig. 1, when water was used as an absorbing solution,
(NH4)2CO3). Vessels were closed, positioned in the rotor, and pressur-
recoveries for L-T4 were lower than 40%. Probably, this behavior is
ized with 20 bar of oxygen. The rotor with the vessels was placed inside
related to the low potential hydrogenionic of the solutions obtained
of the microwave oven, and the heating program (1400 W for 5 min,
after digestion of both samples by the MIC (pH < 3.0). In this
and 0 W for 20 min for cooling) was started [24,29]. After combustion,
condition, the conversion of I to volatile species, such as HI and I2,
the pressure of each vessel was released and resultant solutions were
is favored, and so the analyte may be lost by volatilization, even using
transferred to volumetric asks and diluted with water up to 25 mL for
closed vessels. Thereby, the water is not a suitable solution for the
subsequent I determination by ISE and IC. The indirect quantication
absorption of I during digestion of commercial L-T4 drugs by the MIC.
of L-T4 in the analyzed samples was carried out by calculations that
Although good recoveries (97101%) had been obtained for L-T4
related to the I concentration in the samples with I content in the drug
using (NH4)2CO3 solutions (50, 100 or 150 mmol L1) during digestion
molecule, as well as with the molecular mass of L-T4.
of the sample containing 100 g of L-T4/tablet, the same behavior was
The accuracy of the proposed method was evaluated by analyte
not observed for the drug containing 200 g of L-T4/tablet. For the
recovery tests. For this, a reference solution containing 1875 mg L1 L-
sample containing the higher dosage of L-T4, quantitative recoveries
T4 (100 L) was added on the sample (400 mg) before digestion by the
only were obtained (99 9%) when 150 mmol L1(NH4)2CO3 was used
MIC for the subsequent I determination by ISE and the indirect
as an absorbing solution. This behavior can be associated with the
quantication of L-T4.
increase of iodine content, which requires the use of more concentrated
All statistical calculations were performed using the software
solutions for its absorption.
GraphPadInStat (GraphPadInStat Software, Inc., version 3.00, 1997),
and a condence level of 95% was used.

3. Results and discussion

3.1. Commercial L-T4 drugs digestion by the MIC preliminary


For the digestion of the L-T4 drugs by the MIC, initial experiments
were carried out to evaluate a suitable way to insert samples into the
combustion system. Initially, the digestion of a commercial tablet was
evaluated, and 100 mg of sample (medium mass per commercial
tablet) was successfully burned. However, in order to digest a higher
sample mass, the samples were comminuted and wrapped with PE
lms before being inserted in the combustion system. Polyethylene
lms were used as described in a previous work [30]. Moreover, in Fig. 1. Recoveries for L-T4 after the digestion of commercial drugs containing 100 g of
these experiments, 50 L of 6 mol L1 NH4NO3 solution were used as L-T4/tablet or 200 g of L-T4/tablet by MIC using water or 50, 100 or
igniter, the initial pressure of O2 was 20 bar, and 6 mL of water were 150 mmol L1 (NH4)2CO3 as an absorbing solution. Determination by ISE (sample mass:
used as the absorbing solution [26,33]. By using these conditions, it 400 mg, n=3).

M.F. Mesko et al. Talanta 166 (2017) 223227

Table 2 4. Conclusion
Iodine and L-T4 concentrations in L-T4 commercial drugs after MIC digestion using
150 mmol L1 (NH4)2CO3 as absorbing solution, and I- determination by ISE (mean
The proposed MIC method was suitable for the digestion of
standard deviation, n=3).
commercial L-T4 drugs for the subsequent determination of I by
Brand Informed L-T4 I (g/tableta) Calculated L-T4 potentiometry with ISE and the indirect quantication of L-T4. Using
concentration (g/tableta) concentration (g/tableta) the proposed method, it was possible to obtain low blank values and
LODs. Moreover, the MIC, combined with ISE, presents a high
A 25 15.1 0.6 23.6 0.9
50 30.1 1.2 47.0 2.0 throughput and a suitable accuracy and precision, allows the use of
100 58.5 1.6 91.3 2.6 an absorbing solution suitable to the analytes and the determination
150 91.9 3.0 143 5 technique, as well as the use of diluted solutions according to green
200 125 2 197 3 chemistry.
B 25 14.6 1.1 23.0 1.7
In addition, it is important to mention that the MIC enables the
200 123 1 192 2
C 25 14.6 1.2 23.0 1.9 complete digestion of the organic matter, ensuring total conversion of
200 93 4 154 5 the iodine present in L-T4 molecules to iodide (iodine specie deter-
mined by ISE). Additionally, the use of the MIC reduces the occurrence
Tablet: equivalent to a tablet with mass of approximately 100 mg. of chemical species related to incomplete digestion of the sample,
which can cause interferences during I determination by ISE and,
Thus, the 150 mmol L1 (NH4)2CO3 was selected as the absorbing consequently, in the indirect determination of L-T4. Another important
solution because this solution provided quantitative recoveries, even aspect is the possibility of evaluating tablets with several concentra-
when drugs containing high concentrations of L-T4 were digested by tions of L-T4 in view that this characteristic allows the quality control of
the MIC. In this condition, probably, I released from the sample during these drugs, which present dosages in micrograms and a narrow
the combustion process was quantitatively converted to I-, allowing the therapeutic index.
determination of I in all commercial L-T4 drugs by ISE. In addition, for
optimized conditions, relative standard deviations were lower than Acknowledgements
10% and a LOD of 11.2 g/tablet for L-T4 (LOD for I-: 7.14 g/tablet)
was obtained, which is at least two times lower than concentration of L- The authors are grateful to CAPES, CNPq and FAPERGS for
T4 in evaluated drugs. Thus, the proposed method can be considered supporting this study.
suitable for L-T4 determination at low concentrations. The LODs were
calculated from the mean of the blank values and the standard References
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