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org/jchemeduc Laboratory Experiment

Determination of Zinc Oxide in Pharmaceutical Preparations by

EDTA Titration: A Practical Class for a Quantitative Analysis Course
Gustavo Borges Simões, Paulo Victor e Silva Badolato, Marcelo Dante Ignać io,
and Eduardo Coelho Cerqueira*
Cite This: https://dx.doi.org/10.1021/acs.jchemed.9b00939 Read Online

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ABSTRACT: Zinc oxide is a common additive in food, cosmetics, and

medicines. Here, we describe the validation of methods to analyze two
pharmaceutical samples containing ZnOtalc powder and dermal
ointmentby ethylenediaminetetraacetic acid (EDTA) titration. The
methods developed were implemented as a practical class to students of
a Quantitative Analysis course, and the statistical analysis of the results
were performed with the students in order to compare experimental results
with label information. The practical class allowed students to see an
interesting application of EDTA titration in quality control and provided
better practical comprehension of important contents in complexometric
titrations, statistical analysis, and laboratory techniques.

KEYWORDS: Second-Year Undergraduate, Upper-Division Undergraduate, Analytical Chemistry, Laboratory Instruction,

Hands-On Learning/Manipulatives, Titration/Volumetric Analysis, Coordination Compounds

■ INTRODUCTION
Complexometric titration is an essential topic in Quantitative
Analysis and is usually applied to the determination of metallic
ions.1−3 Typical quantitative analysis practical classes involve
titrations with the chelating agent ethylenediaminetetraacetic
acid (EDTA), such as analysis of metal alloys,4,5 determination
of water hardness,6 and analysis of calcium in food and
supplements.7
To keep students’ enthusiasm in the practical classes and
highlight applications of titrations in quality control, it is
suggested that more daily use samples are analyzed in practical
classes.3,8 In this work, we propose a method to determine zinc
oxide in two pharmaceutical preparationstalc powder and
dermal ointmentby classical EDTA titration. A practical
class using this analytical method is proposed and applied in
the Quantitative Analysis discipline to students of the chemical
technician course in the Instituto Federal de Educaçaõ , Ciência
e Tecnologia do Rio de Janeiro (IFRJ), Campus Rio de
Janeiro, Rio de Janeiro, Brazil.
Zinc oxide (ZnO) is a white powder with vast applications
in pharmaceutical products due to its antiseptic, drying, anti-
inflammatory, deodorant, ultraviolet protection, and skin
redness healing properties.9,10 It is also a source of zinc, a
necessary mineral. However, zinc can be toxic in the case of
exposure at higher concentrations than physiological needs.11
Therefore, it is extremely important to quantify zinc in
pharmaceutical preparations using analytical methods.
© XXXX American Chemical Society and
Division of Chemical Education, Inc.
A J. Chem. Educ. XXXX, XXX, XXX−XXX
Several instrumental methods are known to be efficient in
zinc determination in pharmaceutical samples, such as
ultraviolet/visible spectrophotometry,11,12 flame atomic ab-
sorption spectrometry,13−17 and inductively coupled plasma-
mass spectrometry (ICP-MS).17,18 Although instrumental
methods have greater sensitivity and reduced time of analysis,
expensive instrumentation, constant maintenance, and techni-
cal training are required.
Classical titrimetric methods are still largely used in quality
control because of their simplicity, low cost, high accessibility,
and accuracy in the analysis of samples with high
concentrations of analyte, such as the active ingredient of
drugs.2,3 They also offer students an important technical
development and set basic concepts for instrumental analysis.
Titrimetric methods for Zn(II) ions usually consist of EDTA
titration at pH 5 using xylenol orange indicator or at pH 10
using eriochrome black-T (EBT) indicator.2,19,20 An advantage
of EBT indicator is that it can also be used for the
determination of water hardness and for EDTA stand-
ardization; hence, it is a common indicator in any analytical
chemistry laboratory.
Received: October 6, 2019
Revised: December 30, 2019
https://dx.doi.org/10.1021/acs.jchemed.9b00939
Journal of Chemical Education
Figure 1. Initial and turning point colors of EBT indicator in the Zn(II) titration with EDTA at pH 10 in the absence (left photo) or presence
(right photo) of Martius Yellow auxiliary indicator.
The analytical method proposed here is based on the
extraction of ZnO present in the pharmaceutical sample by
diluted HCl and titration with EDTA in the presence of EBT
indicator at pH 10. The students then calculate the ZnO
content in the sample and compare the experimental results
with the product label information by calculating the percent
of deviation and the confidence interval using Microsoft Excel.
The class can be completed in a 4 h laboratory period,
including the statistical analysis, and does not require advanced
instrumentation. Students enjoyed the activity, which allowed
them to apply quantitative and statistical analysis in quality
control of a daily use sample. This new practice is currently
applied every semester to the classes of the integrated and
concomitant/subsequent chemical technician course in IFRJ
Campus Rio de Janeiro.
■ EXPERIMENTAL PROCEDURE
Reagents and Solutions
All reagents were obtained from Sigma-Aldrich and were used
without further purification. Solutions were prepared in
deionized water. The preparation of ZnO standard, EDTA
solution, Martius Yellow auxiliary indicator, EBT indicator, and
ammonia buffer are described in the Supporting Information.
ZnO based talc powder and ointment samples were obtained
at a local drugstore. Products label information can also be
found in the Supporting Information.
Extraction of ZnO from Talc Powder Sample (Powder
Method)
Since ZnO is an amphoteric oxide, it can react with both acids
and hydroxides. Equation 1 represents the extraction of Zn(II)
ions in acid medium.
ZnO(s) + 2H+(aq) → Zn 2 +(aq) + H 2O(l) (1)
About 1.0 g of talc powder is weighed to 0.1 mg in a 250 mL
beaker, to which 50 mL of 9% hydrochloric acid is added. The
mixture is stirred with a glass rod for 10 min, transferred
quantitatively to a 250.00 mL volumetric flask and diluted to
the mark. Finally, the suspension is filtered through a
qualitative filter paper to a 400 mL beaker, generating a clear
solution containing extracted Zn(II) from the sample.
pubs.acs.org/jchemeduc Laboratory Experiment
Extraction of ZnO from Dermal Ointment Sample
(Ointment Method)
About 0.6 g of dermal ointment is weighed to 0.1 mg in a 250
mL beaker, where 50 mL of 9% hydrochloric acid and 50 mL
of diethyl ether are added inside a fume hood. The function of
the diethyl ether is to extract organic components from the
ointment, dismantling it and allowing the access of hydro-
chloric acid to the zinc oxide.12 A magnetic bar is added, and
the mixture is stirred on a magnetic stirrer for 1 h in a fume
hood. The resulting suspension is transferred to a separatory
funnel, and the denser aqueous phase is collected in a 250.00
mL volumetric flask. The separatory funnel is washed three
times with 20 mL of saturated NaCl solution. The additional
aqueous phases are collected in the volumetric flask, that is
diluted to the mark, generating a clear solution containing
extracted Zn(II) from the sample.
Preparation of Zn(II) Standard Solutions
About 0.24 g of pure zinc oxide is weighed to 0.1 mg in a 250
mL beaker and treated according to either the powder or the
ointment method, producing 500.00 mL of Zn(II) standard
solutions at about 0.006 mol L−1.
Titration
Aliquots of 20.00 mL of the samples containing Zn(II) are
taken using a volumetric pipet and transferred to a 250 mL
erlenmeyer flask, to which 10 mL of ammonia buffer at pH 10,
two drops of EBT indicator, and five drops of Martius Yellow
auxiliary indicator (optional) are added. The solution should
have a red color at his point. Auxiliary indicators are not
sensible to the complexation reactions occurring in the
reaction medium and have the sole function of improving
the visualization of the titration’s end point. In this case,
instead of the typical magenta to blue transition of the EBT
indicator, the addition of Martius Yellow turns the color
change from red to green, as shown in Figure 1. The mixture is
titrated with a 0.01 mol L−1 standardized solution of EDTA in
triplicate using a 25 mL buret until pure green color. A blank
titration was performed using 20.00 mL aliquots of 1.8% HCl
instead of Zn(II) sample. The mass of ZnO (mZnO, in mg) in
the sample can be calculated by eq 2:
V
mZnO = C EDTA(VT − VB)M ZnO
V0 (2)
where CEDTA is the concentration of standardized EDTA, in
mol L−1; VT and VB are the average volumes of EDTA
B https://dx.doi.org/10.1021/acs.jchemed.9b00939
J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
pubs.acs.org/jchemeduc
consumed in the sample and in the blank titrations,
respectively, in mL; MZnO is the molar mass of ZnO (81.379
g·mol−1); V is the volume of the volumetric flask in which the
Zn(II) sample solution was prepared, in mL; and V0 is the
volume of the aliquot taken of Zn(II) solution, in mL.
Method Validation
Prior to the experimental class with students, the methods
were validated in terms of linearity (by the coefficient of
determination of an obtained versus expected ZnO mass linear
fit), precision (by the RSD, relative standard deviation) and
accuracy (by the percentage of deviation from label
values).19,20 This section is described in depth in the
Supporting Information.
Application of the Experiments by Students
As mentioned above, the procedures were applied by students
of the chemical technical course of IFRJ, Campus Rio de
Janeiro, in Quantitative Analysis classes. The data provided in
this article were obtained from a group of 22 students for the
powder method and of 8 students for the ointment method in
April of 2017 in 4 h of laboratory time. Initially, the practice
theory was explained, including the importance of zinc oxide in
the pharmaceutical industry, the process of zinc oxide
extraction with HCl, the reasons for using ammonia buffer
and auxiliary indicator, the turning point colors by showing
previously prepared color standards by the laboratory
assistants, and calculations of ZnO content (30 min). The
practice was conducted in the following order: weigh the
sample; perform the extraction; prepare material for titration
during filtration in case of talc, or during extraction in the case
of ointment; and titration (2 h). The buffer and the indicator
solutions were previously prepared by the laboratory assistants.
All students performed their own three titrations, although, the
EDTA solution and the extracted Zn(II) solution were shared
by groups of two students. The 0.01 mol L−1 EDTA solution
was standardized with calcium carbonate primary standard and
murexide indicator in the previous class, as described in the
Supporting Information. Basics for calculation of standard
deviation, RSD, and confidence interval were taught after the
practice and performed using Microsoft Excel (1 h).21−23 After
2 weeks, the students turned in a report containing all collected
data, calculation of ZnO content, and conclusion of the
analysis. The worksheet containing RSD and confidence
interval calculation was sent apart from the report by email.
■
HAZARDS
Diethyl ether is highly flammable and should be stored away
from any source of heat and oxidizing reagents in a cool and
well-ventilated area. It is also highly volatile and toxic. For
these reasons, the ointment method was applied to a smaller
group of students. Hydrochloric acid and ammonium
hydroxide are corrosive and volatile. These reagents must
always be manipulated in a fume hood with safety gloves, safety
goggles, and laboratory coat. Avoid inhalation and skin contact.
EDTA can be irritant to the skin. It is advised to handle it with
gloves. Diethyl ether was disposed in nonchlorinated organic
waste flask. Remaining solutions of Zn(II) in HCl and EDTA
titrated solutions were mixed and neutralized to pH 6 to 9 for
disposal in the sink.
C https://dx.doi.org/10.1021/acs.jchemed.9b00939
■
Laboratory Experiment
RESULTS AND DISCUSSION
Method Validation
The linearity curve obtained is given in Figure 2. The
coefficient of determination (r2) for the powder and the
Figure 2. Linearity curve. Aliquots of 5, 10, 20, 25, or 30 mL of
standard solutions of Zn(II) were analyzed by EDTA titration and the
mass of ZnO in each aliquot is plotted against the expected mass. The
r2 values of the linear fits are shown in blue for powder and red for
ointment methods and are above 0.99, which indicates that both
methods are linear in this working range.
ointment methods were 0.9999 and 0.9993, respectively, in the
working range (50 to 150% of working concentration). This is
higher than the minimum accepted value of 0.99 for a linear
method, so the method can be considered linear in the range
analyzed.21,22
Table 1 shows the results obtained for three analyses in
three levels of concentration of Zn(II) (10, 20, and 25 mL
aliquots of Zn(II) solution). The masses of ZnO obtained are
expressed in the same unit given in the labels of the products
for comparison purposes.
Precision and accuracy of the methods were evaluated by
RSD and percentage of deviation, respectively. All RSD values
obtained for both methods were below 1%, indicating that the
method has high precision, since the acceptable values are
below 5%.21,22 As for the percentage of deviation, the results
are also satisfactory, with deviations from each product label
information of less than 1% in all levels of concentration for
the talc method and less than 5% in all levels for the ointment
method.21,22 This suggests that both methods are precise and
accurate. Considering these results, both methods were
effectively validated.
Application of the Experiments to Students
The results of the students’ analysis of talc and ointment are
shown in Tables 2 and 3, respectively. Each result represents
the average of three separate determinations made by each
student. The RSD values varied from 0.21 to 1.78% for the
powder method and from 0.22 to 1.41% for the ointment
method. As for the percent of deviation from the label data, the
values obtained for the talcum powder and the dermal
ointment showed a variation from −7.32 to 7.39%, and from
−6.08 to 3.37%, respectively. In the talcum powder analysis,
only 4 out of 22 analysis resulted in a deviation greater than
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Journal of Chemical Education pubs.acs.org/jchemeduc Laboratory Experiment

Table 1. Comparative ZnO Amounts Obtained for the Analysis of Talc Powder and Dermal Ointment in 3 Levels of
Concentrations in Triplicates
Powder Method
Aliquot Volume of Sample Solution Mass of ZnO (g/100 g of Talc Powder) RSD Deviation
mL Triplicate (Titrimetric) Average (Titrimetric) Label % %
10 11.78 11.78 11.69 11.75 11.735 0.44 0.14
20 11.78 11.86 11.87 11.84 0.42 0.86
25 11.76 11.76 11.73 11.75 0.15 0.13
Ointment Method
Aliquot Volume of Sample Solution Mass of ZnO (g/g of Dermal Ointment) RSD Deviation
mL Triplicate (Titrimetric) Average (Titrimetric) Label % %
10 0.2021 0.1957 0.1973 0.1984 0.200 1.68 0.80
20 0.1941 0.1916 0.1941 0.1933 0.61 3.35
25 0.1957 0.1928 0.1984 0.1956 1.17 2.20

Table 2. Comparison of ZnO Amounts Obtained by the technical instrumentation mistakes, loss of sample during
Students Using the Powder Method diethyl ether extraction; and surpassing the end point of the
titration. The results were expressed as average mass of ZnO in
Mass of ZnO Obtained, by Powder Deviation from
Method, g RSD, %a Label, %a 100 g of talc or in 1 g of ointment ± confidence interval as
shown at the end of Tables 2 and 3. The average RSD and the
12.30 1.10 4.84
percentage of deviation considering all students’ results were
12.60 0.48 7.39
also calculated. For the talc and ointment analysis the results
11.69 0.25 −0.41
were, respectively, 11.84 g ± 0.20 g (label: 11.735 g), with an
11.35 0.51 −3.27
RSD of 3.89% and deviation of 0.89% and 0.2005 g ± 0.0063 g
12.51 0.46 6.60
(label: 0.200 g), with an RSD of 3.86% and deviation of 0.25%.
12.26 0.77 4.46
Overall, the results are in good accordance with the label
11.96 1.18 1.89
values.
11.21 0.41 −4.44
11.52 0.26 −1.81 Application of the Methods over the Period of 2017−2019
12.01 1.24 2.35 The powder method can be easily applied to graduate or
12.12 0.25 3.28 technician courses in Chemistry or related areas, such as
11.84 0.25 0.87 Pharmacy. The reagents and material required have low risk,
12.02 1.01 2.42 are inexpensive, and accessible. The sample preparation is
12.11 1.00 3.16 interesting because it contains extraction and filtration steps,
11.03 0.00 −6.00 which are important to remove matrix interferences and differs
10.88 0.00 −7.32 from the common dilute and titrate aspect of some
11.82 1.78 0.72 experimental classes in Quantitative Analysis.
12.08 1.19 2.35 This determination of ZnO in talc powder was well-accepted
11.80 0.21 0.52 by other professors that administer the quantitative analysis
11.67 0.39 −0.59 discipline and replaced a former one, the goal of which was to
11.39 0.78 −2.94 simply determine the percentage of Zn2+ in an aqueous
12.27 1.51 4.59 solution of zinc sulfate prepared in the laboratory. It is
a
Confidence interval: 11.84 ± 0.20. currently applied every semester to the classes of the integrated
and the concomitant/subsequent chemical technician courses
Table 3. Comparison of ZnO Obtained by the Students in IFRJ Campus Rio de Janeiro.
Using the Ointment Method Professors report as the main positive aspects of the practice:
working with a daily use sample; the fact that results obtained
Mass of ZnO Obtained, by Ointment Deviation from are in accordance with label information; and the application
Method, g RSD, %a Label, %a
of relevant topics of complexometric titration, specifically, the
0.1935 0.65 3.23
use of ammonia buffer as an auxiliary complexing reagent and
0.1982 0.48 0.90
the use of an auxiliary indicator. They also mention that the
0.1933 0.98 3.37
practice is important for technical development of students due
0.1938 1.12 3.09
to the extraction and filtration steps. All students enjoyed the
0.2020 1.41 −1.01
activity and report as positive aspects the use of a daily sample,
0.1991 0.56 0.44
and the learning of parameters such as confidence interval and
0.2122 0.22 −6.08
RSD, which were new to them. As negative aspects, both
0.2119 0.39 −5.94
professors and students report the time-consuming filtration
a
Confidence interval: 0.2005 ± 0.0063. step and difficulties of students to fill the volumetric flask to
the mark due to the formation of some foam on top of the
5%, and for the ointment analysis, it happened for two out of solution.
eight analysis. Abnormal values may have been obtained due to For the ointment method, the extraction with ether and HCl
students’ inexperience that can lead to sample contamination, step makes the practice longer, with a laboratory duration of
D https://dx.doi.org/10.1021/acs.jchemed.9b00939
J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education pubs.acs.org/jchemeduc
almost 3 h. Handling diethyl ether is another issue, since it is
highly volatile and requires space in the fume hood for all
students, thus limiting the number of students in class. Despite
these disadvantages, the extraction is efficient and didactic,
teaching the students a way to extract compounds from
ointments and pastes. It also links analytical and organic
chemistry techniques. All students enjoyed the practice for the
same reasons as the powder method, but report a difficulty in
weighing the ointment, since it sticks to the spatula and in the
inner walls of the Erlenmeyer flask. Some of them also
complained about the odor of diethyl ether after taking the
extracted samples from the fume hood for titration. Because of
these difficulties, and the existence of the safer powder method,
the ointment method was not applied as a routine practical
class, but was used as a discipline project with small group of
students.
■ CONCLUSION
The experiment proposed here contemplates an essential topic
in Quantitative Analysis, complexometric titrations, using a
realistic sample. It illustrates good methods for the extraction
of components from pharmaceutical samples in different
statesa powder and an ointmentand applies techniques
such as filtration, extraction, and titration. The students have
also learned how to evaluate if an experimental method is
precise and accurate and how to statistically compare
experimental and expected values.
The proposed methods of determination of ZnO in talc
powder and dermal ointment samples were effectively
validated in terms of linearity, precision, and accuracy. The
implementation of this experiment in the Quantitative Analysis
course to students of chemistry technical courses of IFRJ was
successful. The powder method was readily accepted as a new
complexometric titration practice for the discipline by the
quantitative analysis team. The ointment method offers more
risks due to the use of a toxic and flammable solvent, diethyl
ether, and should be applied with more caution and to smaller
groups of students. The final experimental ZnO contents
obtained by the students were considered precise and accurate.
The importance of using realistic samples in analytical
chemistry classes has been suggested to engage students and
improve learning. Considering this, working with talc powder
and dermal ointment in the context of quality control using
complexometric titration resulted in a very didactic and career
relevant activity in which chemistry students were highly
involved.
■
ASSOCIATED CONTENT
* Supporting Information
sı
The Supporting Information is available at https://pubs.ac-
s.org/doi/10.1021/acs.jchemed.9b00939.
Notes for instructor; summary about complexometric
titrations; reagents preparation; possible experimental
variations; sample details (PDF, DOCX)
Method validation criteria (PDF, DOCX)
■
AUTHOR INFORMATION
Corresponding Author
Eduardo Coelho Cerqueira − Instituto Federal de Educaçaõ ,
Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro
E https://dx.doi.org/10.1021/acs.jchemed.9b00939
Laboratory Experiment
20270021, Brazil; orcid.org/0000-0001-8944-7922;
Email: eduardo.cerqueira@ifrj.edu.br
Authors
Gustavo Borges Simões − Instituto Federal de Educaçaõ ,
Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro
20270021, Brazil
Paulo Victor e Silva Badolato − Instituto Federal de Educaçaõ ,
Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro
20270021, Brazil
Marcelo Dante Ignácio − Instituto Federal de Educaçaõ ,
Ciência e Tecnologia do Rio de Janeiro, Rio de Janeiro
20270021, Brazil
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.jchemed.9b00939
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We acknowledge the students from the classes QM161 and
PMQ351 of 2017.1 of IFRJ Campus Rio de Janeiro, who
participated in the analysis described, the quantitative analysis
team of IFRJ Campus Rio de Janeiro, and the institution itself
for the support.
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