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An Indirect Atomic Absorption Spectrophotometric Determination of

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DOI: 10.1007/s13369-011-0058-4

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An Indirect Atomic Absorption
Spectrophotometric Determination
of Trifluoperazine Hydrochloride in
Pharmaceuticals

Ameen Q. Waleed, Zuhair A-A. Khammas,

Ashraf S. Al-Ayash & Fadhel Jasim

Arabian Journal for Science

and Engineering

ISSN 1319-8025

Arab J Sci Eng

DOI 10.1007/
s13369-011-0058-4

1 23
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Arab J Sci Eng
DOI 10.1007/s13369-011-0058-4

R E S E A R C H A RT I C L E - C H E M I S T RY

Ameen Q. Waleed · Zuhair A-A. Khammas ·

Ashraf S. Al-Ayash · Fadhel Jasim

An Indirect Atomic Absorption Spectrophotometric

Determination of Trifluoperazine Hydrochloride
in Pharmaceuticals

Received: 2 December 2009 / Revised: 18 May 2010 / Accepted: 25 May 2010

© King Fahd University of Petroleum and Minerals 2011

Abstract A new method was developed for the determination of trifluoperazine hydrochloride (TFPH) at
trace levels in pharmaceuticals. This method involved formation of a TFPH-Pt(IV) complex at a specific pH,
and extraction of this complex into an organic solvent. Flame atomic absorption spectrometry was used to
measure the absorbance of platinum in the complex, and indirectly determine the concentration of TFPH.
Under the optimized conditions, the linear dynamic range, detection limit, relative standard deviation (n = 5),
and the recoveries of the standard addition method were 2−60 µg mL−1 , 0.085 µg mL−1 , 1.58−2.03, and
102.24 ± 0.43, respectively. The proposed method was applied to the determination of TFPH in the drug
Stelazine (5 mg of TFPH per tablet) by both direct and standard addition procedures and gave results of 4.89
and 4.88 mg of TFPH per tablet. This method was compared statistically with the determination of TFPH by
UV–Vis spectroscopy, and the difference in the precision from these methods was insignificant at the 95%
confidence level.
Keywords Trifluoperazine hydrochloride · Platinum(IV) · Stelazine · Atomic absorption spectroscopy ·
Indirect method

A. Q. Waleed
Baghdad College of Pharmacy, Bab Al- Muadha’am, Baghdad, Iraq

Z. A.-A. Khammas (B)

Department of Chemistry, College of Science for Women, University of Baghdad,
Jadiriyia, Baghdad, Iraq
E-mail: dr_zuhair52@yahoo.com

A. S. Al-Ayash · F. Jasim
Department of Chemistry, College of Science, University of Baghdad,
Jadiriyia, Baghdad, Iraq

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1 Introduction

Trifluoperazine hydrochloride (10-[3-(4-methylpiperazin-1-yl) propyl]-2-(trifluoromethyl) phenothiazine

hydrochloride, TFPH, Fig. 1) is a phenothiazine derivative that is widely used for the treatment of schizo-
phrenia, and other psychotic disorders. It has a highly selective mode of action, and produces a tranquil state
of mind without excessive sedation [1,2].

Fig. 1 The chemical structure of trifluoperazine hydrochloride

Many patients that have not responded to other therapies have benefited from this versatile psychotropic
agent. Recently, TFPH has been the focus of extensive research, both for the development of rapid and simple
methods for its detection and because of its structural properties as a reagent for chemical analysis [3]. Vari-
ous methods have been employed for the determination of TFPH including titrimetry [4], potentiometry [5],
spectrophotometry [6–13], fluorimetry [14], flow injection analysis [15,16], sequential injection analysis [17],
high-performance liquid chromatography [18,19] and liquid chromatography electrospray ionization mass
spectrometry (LC–ESI–MS) [20]. Because of its structural features, TFPH and other phenothiazine deriva-
tives have been used extensively as complexing agents with several metals [1,3,8,21–26]. The techniques used
for measurement of TFPH, such as flow injection analysis, sequential injection analysis, high-performance
liquid chromatography, and LC–ESI–MS, all require highly sophisticated instruments that are relatively expen-
sive and not available in all laboratories. By contrast, ultraviolet–visible (UV–Vis) spectroscopy is simple with
sufficient precision and sensitivity, but it does suffer from strong interferences from drug excipients and dil-
uents [27]. Many laboratories are able to perform atomic absorption spectroscopy (AAS), which is a simple
technique that is very attractive for a wide range of applications. AAS can be used in direct detection of metals
and indirect analyses of organic compounds such as medicines [28–32].
To date, AAS has not been used for the determination of TFPH in pharmaceutical preparations. An AAS
method for the detection of TFPH would be attractive as a simple, sensitive, reliable, and inexpensive method.
Investigation of such a method could be used to improve the performance and use of AAS in pharmaceutical
analyses, particularly for cases where UV–Vis spectroscopy is unavailable in the laboratory for the routine
determination of drugs.
In the present work, an accurate indirect AAS method for detection of TFPH in pure and pharmaceutical
(Stelazine) samples was developed. This method is based on the reaction of TFPH with platinum(IV) in an
acidic medium to form a TFPH complex. The complex was extracted into benzyl alcohol and aspirated into
air/acetylene flame for indirect assay of TFPH via AAS of the platinum metal. The proposed method was
compared statistically with UV–Vis spectroscopy.

2 Experimental

2.1 Apparatus

Atomic absorption spectroscopy measurements were carried out on a GBC 933 Plus spectrophotometer (GBC
Scientific Equipment, Melbourne, Australia) equipped with a background corrector, GBC D2 Lamp, and plat-
inum hallow cathode lamp (Shimadzu, Kyoto, Japan) under the following conditions: wavelength 266 nm,
lamp current 10 mA, slit width 0.2 nm, air/acetylene flame ratio 8/2. All the UV–Vis spectroscopy measure-
ments were carried out using a Shimadzu UV-160 spectrometer equipped with a 10 mm matched quartz cell.
UV–Vis spectra were obtained of the 200 mg L−1 TFPH standard solution and the TFPH-Pt(IV) complex in
benzyl alcohol. The Fourier transform infrared (FTIR) spectrum of the complex was recorded on a Shimadzu

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FT-IR8000 spectrometer. A Jenway 3020 pH meter (Bibby Scientific, Stone, UK) with a combined electrode
was used for pH measurements.

2.2 Reagents and Chemicals

All the chemicals used were of analytical reagent grade, and deionized water was used for diluting the reagents
and samples. Pure TFPH and Stelazine were provided from the State Company for Drug Industries and Med-
ical Appliances (Samarra, Iraq). A standard platinum solution (1,000 µg mL−1 ), hydrochloric acid solution
(36.4%), and benzyl alcohol were purchased from B.D.H Middle East LLC (Dubai, UAE). TFPH standard
solution (1,000 µg mL−1 ) was prepared by dissolving 0.1 g of pure TFPH in a suitable volume of water and
then diluting to 100 mL in a volumetric flask. A working platinum standard (100 µg mL−1 ) was prepared by
diluting the stock solution with water.

2.3 Procedures

2.3.1 Direct Calibration Method

Aliquots (10–300 µL) of a stock standard solution of TFPH (2–60 µg mL−1 TFPH) were transferred into
5 mL volumetric flasks. Platinum solution (1.15 mL of the 100 µg mL−1 solution) was added to each flask,
and the pH was adjusted to 1.6 using dilute HCl or NaOH solution. The solutions were set aside for 4 min, and
then diluted to 5 mL with water. The mixtures were heated in a water bath at 85◦ C for 4 min. After cooling,
each solution was extracted with 1 mL of benzyl alcohol after shaking for 1 min. The organic layer from
each solution was transferred into a test tube, and then aspirated into an air/acetylene flame. The AA signals
were measured at 266 nm. Curves were plotted of the absorbance (in peak height mode) against the TFPH
concentration, and the corresponding linear regression equation was used to convert the absorbance into TFPH
concentration for all the Stelazine samples.

2.3.2 Preparation of Stelazine Tablets

Twenty tablets of Stelazine were crushed to a powder in a clean agate mortar and triturated well. A quantity
of the fine powder (0.4518 g) was dissolved in a sufficient volume of water with continuous shaking, and then
filtered. The filtrate was transferred into a 50 mL volumetric flask and diluted to the mark with water.

2.3.3 Standard Addition Method

Aliquots of the Stelazine sample solution (Sect. 2.3.2) were pipetted into seven 5 mL calibrated flasks containing
0.000, 0.250, 0.375, 0.500. 0.750, 1.000, or 1.500 mL of TFPH (200 µg mL−1 ). Then 1.15 mL (100 µg mL−1 )
of platinum solution was added to each flask and the pH was adjusted to 1.6 using dilute HCl or NaOH solution.
Each flask was set aside for 4 min, diluted to the mark with water and mixed well. The solutions were extracted
and analyzed as in the direct calibration procedure (Sect. 2.3.1).

2.3.4 Statistical Analysis

All statistical calculations, such as basic statistics, significance tests, regression equations and correlation coef-
ficients for the calibration curves, were implemented using Minitab version 11 (Minitab Inc., State College,
PA, USA).

3 Results and Discussion

3.1 UV–Vis Spectra

UV–Vis spectra of the pure TFPH and its complex with Pt(IV) were obtained to verify formation of the com-
plex (Fig. 2). The pure drug gave two absorption maxima at 258 and 307 nm, while the spectrum of the pink
chelate showed a new absorption maximum at 520 nm (Fig. 2), which indicates the complex between TFPH
and Pt(IV) formed.

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(a) TFPH
(b) TFPH complex

(a)

Absorbance
(b)

Wavelength (nm)
Fig. 2 UV–Vis spectra of a pure TFPH and b the TFPH-Pt (IV) complex

3.2 Optimization of the Method

3.2.1 Effect of pH

The effect of pH on formation of the TFPH-Pt(IV) complex was determined by recording the AA signals
of platinum from pH 1–3. The acidity of the solution was adjusted with 0.1 mol L−1 HCl. The absorbance
first increased dramatically with increasing pH and reached a maximum at pH 1.6 (Fig. 3). The absorbance
then gradually decreased because of partial dissociation of the complex at higher pH, which may result in
incomplete extraction of Pt as the TFPH complex. Consequently, pH 1.6 was selected as the optimum pH for
complete formation of the complex.

0.16

0.14
Absorbance

0.12

0.10

0.08

0.06
0.80 1.20 1.60 2.00 2.40 2.80 3.20
pH

Fig. 3 Effect of pH on the formation of the TFPH-Pt(IV) complex

3.2.2 Effect of Concentration of the Pt(IV) Solution

The effect of the Pt(IV) concentration was investigated by measuring the AA signal of solutions containing
(30 µg mL−1 ) of TFPH and various amounts of platinum (6–32 µg mL−1 ). The absorbance of the TFPH-
Pt(IV) complex initially increased linearly as the concentration of the Pt(IV) ion increased, and then tapered
off (Fig. 4). The optimum concentration of Pt(IV) was 23 µg mL−1 , and this was selected for complete complex
formation in subsequent experiments.

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0.20

0.16

0.12

Absorbance
0.08

0.04

0.00
0.00 10.00 20.00 30.00 40.00
-1
Concentration of Pt (IV) (µg mL )

Fig. 4 Effect of the concentration of platinum on the determination of TFPH

3.2.3 Effect of the Reaction Time

Figure 5 shows the effect of the reaction time on the formation of the complex before the extraction process
at constant temperature (85◦ C). The absorbance increased rapidly with the reaction time and approached a
plateau at 4 min. Therefore, a reaction time of 4 min was selected for subsequent experiments.

0.20

0.16

0.12
Absorbance

0.08

0.04

0.00
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00
Time (min)

Fig. 5 Effect of the reaction time on the formation of the TFPH-Pt(IV) complex

3.2.4 Effect of Temperature

The effect of temperature on formation of the TFPH-Pt(IV) complex is shown in Fig. 6. In a preliminary
investigation, the reaction between the metal ion and TFPH was very slow and took about 1 h without heating.
The complex formation reaction rate was measured at different temperatures using a fixed reaction time of
4 min. The absorbance was found to increase with increasing reaction temperature and reached a maximum at
85◦ C. Beyond this temperature, the absorbance decreased because of decomposition of the complex.

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0.16

0.14

Absorbance
0.12

0.10

0.08

30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00

Temperature (°C)

Fig. 6 Effect of the temperature on the AA signal of TFPH-Pt(IV)

3.2.5 Selection of the Solvent

This procedure involves measurement of the TFPH-Pt(IV) complex in an organic solvent, and it was necessary
to select a suitable solvent to efficiently, selectively, and quantitatively extract the complex from the aqueous
solution. Consequently, a variety of organic solvents, including o-xylene, toluene, carbon tetrachloride, 1-buta-
nol, cyclohexanone, benzene, acetyl acetone, diethyl ether, benzyl alcohol, dichloromethane, and petroleum
ether were examined. Benzyl alcohol gave higher extraction efficiency (Sect. 3.2.7) of the complex during
one-step extraction and considerably lower extraction of the free reactants than the other solvents investigated.
Solvents such as benzene and o-xylene were excluded because of the unstable flames they produced.

3.2.6 Effect of Extraction Time

The shaking time for complete extraction of the complex was studied. The absorbance of the extract remained
constant between 0.8–4 min (Fig. 7), and 1 min was chosen as an optimum extraction time for use in subsequent
experiments.

0.16
Absorbance

0.15

0.14

0.00 50.00 100.00 150.00 200.00 250.00

Time (s)

Fig. 7 Effect of the extraction time on the determination of the TFPH-Pt(IV) complex

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3.2.7 Effect of the Phase Ratio

This aqueous/organic phase ratio for extraction of the TFPH-Pt(IV) complex was investigated using various
volumes of the aqueous phase (4–8 mL) and 1 mL of the organic solvent. The maximum absorbance was
achieved when the aqueous/organic phase ratio was 5:1 (Fig. 8). From the absorbance data, the percent extrac-
tion (% E) and distribution ratio of the complex were also calculated and found to be 94.69% and 89.16,
respectively, for the one-step extraction.
0.17

0.16
Absorbance

0.15

0.14

0.13

3.00 4.00 5.00 6.00 7.00 8.00 9.00

VL (mL)

Fig. 8 Effect of the ligand volume (VL) on the determination of the TFPH-Pt(IV) complex, where (VM) is the volume Pt(IV)
solution

3.3 Suggested Structure of the Complex

Several spectroscopic techniques, including FTIR, flame AAS and the molar ratio method by UV–Vis spec-
troscopy, were used to elucidate the probable structure of the TFPH-Pt(IV) complex produced. The results
revealed that a 1:1 (metal:drug) complex formed with a stability constant of 7.5 × 107 M−1 at λmax 520 nm
(Fig. 9). The FTIR spectrum of the complex showed that the TFPH aliphatic and aromatic (C-N) bands shifted
0.20

0.19
Absorbance

0.18

0.17

0.16
0.00 0.30 0.60 0.90 1.20 1.50 1.80 2.10
VL/VM

Fig. 9 Molar ratio method for determining the composition of TFPH-Pt(IV) complex

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+2
Cl Cl

Pt

H3C
N _
2Cl
N
F
F
N

Fig. 10 Probable chemical structure of the TFPH-Pt(IV) complex

to 1020 and 1340 cm−1 , respectively, which indicates formation of the complex with Pt ion. The (C-S-C) band
remained unchanged at 754 cm−1 . Two Pt-N bands also appeared at 260 and 290 cm−1 . These results were
used to propose a structure for the complex (Fig. 10).

3.4 Method Validation

Under the optimized conditions, a linear calibration graph was obtained by plotting the AA signal against the
concentration of TFPH. The calibration data are summarized in Table 1. The following regression equation
was obtained:
Y = (0.0055 ± 0.0002) X + (0.0036 ± 0.0062), r = 0.9989 and n = 10
where Y is the AA signal, and X is the TFPH concentration in µg mL−1 . This regression line had a coefficient
of determination (R 2 ) of 99.78%, which suggests it is statistically valid. Beer’s law was obeyed over the con-
centration range 2–60 µg mL−1 . At higher concentrations, the increase in concentration tapered off because of
incomplete dissociation of the analyte, which was limiting at high concentrations [33]. The limit of detection
was 085 µg mL−1 , which is better than that obtained by Basavaiah and Swamy (0.14 µg mL−1 ) using a highly
sensitive spectrophotometric method [4]. However, it is worse than that obtained by Idris (0.018 µg mL−1 )
[17] using on-line coupling of solid-phase extraction, derivatization, and spectroscopy by sequential injection
analysis for the detection of TFPH in human urine.
The accuracy in terms of percent recovery and precision were established using the recommended proce-
dure (Sect. 2.3.3). The results (Table 2) indicated that the indirect flame AAS determination of TFPH was not
greatly affected by the presence of other compounds in the drug sample.

Table 1 Method validation of the AAS determination of the TFPH-Pt(IV) complex using the direct calibration procedure

Parameter Value
Range of concentration (µg mL−1 ) 2–60
Detection limit (µg mL−1 ) for n = 13 0.085
Regression line y = 0.0055x + 0.0036
Correlation coefficient (r) 0.9989
Coefficient of determination (R2 ) 99.78%
C.L. for the slope (b ± tsb ) at 95% 0.0055 ± 0.0002
C.L. for the intercept (a ±tsa ) at 95% 0.0036 ± 0.0062
RSD% (n = 5) 1.94

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Table 2 Accuracy and precision of the proposed AAS method

Amount of Amount of TFPH Rec (%) Erel (%) RSD (%, n = 5) Mean Mean Erel. (%)
TFPH taken (µg mL−1 ) found (µg mL−1 ) Rec (%) S.D.
5 5.18 103.6 3.6 2.03 102.4 ± 0.432 2.24
20 20.73 101.67 1.65 1.92
50 50.73 101.46 1.46 1.58

Table 3 Statistical comparison between the proposed AAS method and UV–Vis

Method Linearity D.L. RSD Correlation Calculated F Tabulated

(µg mL−1 ) (µg mL−1 ) (%) (n = 5) coefficient (r) F44 P = 0.05
UV–Vis method 1–120 0.18 1.89 0.9992 4.65 6.388
AAS-method 2–60 0.085 1.94 0.9989

3.5 Determination of TFPH in Stelazine

The proposed method was applied to the determination of TFPH in Stelazine tablets (5 mg of TFPH per tablet).
Using the direct calibration and standard addition procedures, the results were 4.89 (relative error –2.2%) and
4.88 mg (relative error –2.4%) per tablet, respectively, which agreed with the known content.
The slopes of the direct calibration and standard addition curves (Y = 0.0056X + 0.0546) were equal, and
interferences from other tablet components were insignificant. Thus, the use of direct calibration is adequate
and supports the specificity of the proposed method.
Because most determinations of TFPH have been performed using UV–Vis spectroscopy, this technique
was also used in this study for the determination of TFPH as TFPH-Pt(IV) after taking into account all the
optimized conditions for AAS. The significance of the difference in the results in term of random and system-
atic errors was evaluated at the 95% confidence level. The results obtained by the AAS method and UV–Vis
methods are summarized in Table 3. The difference in the precision for the two techniques was insignificant.
However, the detection limit obtained by the proposed method was half that of the UV–Vis method.
The regression line between the two methods (Fig. 11) was constructed, and indicated that a significant
correlation did not exist between the two methods in the concentration range 5–40 µg mL−1 . This indicates that
were no differences between the two methods for the detection of TFPH in pharmaceutical preparations [34].

45.00

40.00
r= 0.9981
35.00

30.00
UV method

25.00

20.00

15.00

10.00

5.00

0.00
0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00
FAAS Method

Fig. 11 Regression line for comparing the AAS and UV–Vis methods

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The stability of the complex formed with 20 µg mL−1 TFPH in the organic solvent throughout analysis
by AAS and UV–Vis spectroscopy was investigated using the percent recovery at different times. The mean
recoveries for up to 2 h were 100.78 and 90.8% for AAS and UV–Vis measurements respectively. This indi-
cated that the proposed AAS method was more accurate than the UV–Vis method. This may be attributed to
the avoidance of any changes that may occur in UV–Vis methods, such as molecular association between the
ligand and metal ions and/or the interaction among the complex, Pt(IV), and the organic solvent.
Finally, the amount of TFPH in the Stelazine tablets was determined by each method using the direct
calibration curves. The indirect AAS result was 4.89 mg per tablet with a relative error of (–2.2%, and the
UV–Vis spectroscopy result was 4.83 mg per tablet with a relative error of (–3.4%).

4 Conclusion

An indirect AAS method was established for the analysis of TFPH in pure pharmaceuticals. To the best of our
knowledge, this is the first report of the reaction between TFPH and Pt(IV), which is an important metal from
a biological point of view, and its determination by flame AAS. The proposed method is simple, accurate, pre-
cise, sensitive and specific, and can be used for routine quality control of both pure TFPH and pharmaceuticals
without interference from other compounds. The quantity of TFPH detected in Stelazine agreed with that stated
by the manufacturer. Furthermore, because of its low detection limit compared with UV–Vis spectroscopy, the
indirect AAS method could be applied to biological samples.

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