Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 141 (2015) 64–70

Contents lists available at ScienceDirect

Spectrochimica Acta Part A: Molecular and

Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa

A rapid Fourier-transform infrared (FTIR) spectroscopic method for

direct quantification of paracetamol content in solid pharmaceutical
formulations
Muhammad Ali Mallah a,⇑, Syed Tufail Hussain Sherazi a, Muhammad Iqbal Bhanger b,
Sarfaraz Ahmed Mahesar a, Muhammad Ashraf Bajeer a
a
National Centre of Excellence in Analytical Chemistry, University of Sindh Jamshoro, Pakistan
b
HEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, 75270, Pakistan

h i g h l i g h t s g r a p h i c a l a b s t r a c t

 FTIR spectroscopic method for rapid

quantification of paracetamol
content.
 Two chemometric models employed
for the quantification in the region
1800–1000 cm1.
2
 The regression coefficient (R ) was Active
achieved 0.999. Ingredient
 The interference study revealed
minimal effect from sample matrix. FTIR Spectroscopy
 The method is green avoiding large
volumes of hazardous solvents for
extraction.

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

Article history: A transmission FTIR spectroscopic method was developed for direct, inexpensive and fast quantification
Received 14 July 2014 of paracetamol content in solid pharmaceutical formulations. In this method paracetamol content is
Received in revised form 17 January 2015 directly analyzed without solvent extraction. KBr pellets were formulated for the acquisition of FTIR spec-
Accepted 20 January 2015
tra in transmission mode. Two chemometric models: simple Beer’s law and partial least squares
Available online 28 January 2015
employed over the spectral region of 1800–1000 cm1 for quantification of paracetamol content had a
regression coefficient of (R2) of 0.999. The limits of detection and quantification using FTIR spectroscopy
Keywords:
were 0.005 mg g1 and 0.018 mg g1, respectively. Study for interference was also done to check effect of
FTIR spectroscopy
Transmission
the excipients. There was no significant interference from the sample matrix. The results obviously
Paracetamol showed the sensitivity of transmission FTIR spectroscopic method for pharmaceutical analysis. This
Pharmaceutical analysis method is green in the sense that it does not require large volumes of hazardous solvents or long run
Quantitative analysis times and avoids prior sample preparation.
Green method Ó 2015 Elsevier B.V. All rights reserved.

Introduction the important drug having antipyretic and analgesic properties

Paracetamol (acetaminophen) is an acylated aromatic amide
and its chemical structure is given the in the Fig. 1. It is one of
⇑ Corresponding author at: National Centre of Excellence in Analytical Chemistry,
University of Sindh, Jamshoro 76080, Pakistan. Tel.: +92 22 9213429; fax: +92 22
9213431.
E-mail address: chemist_ali2007@yahoo.com (M.A. Mallah).
most frequently prescribed throughout the world. It has been
proved to be extremely efficient for the mild pain relief, muscular
aches, neuralgia, migraine headache, rheumatic pain, fever and
osteoarthritis. Paracetamol and opioid analgesics combination is
sometimes used to treat surgical pain and also to provide palliative
care for cancer patients at advanced stages. It is also one of the
major ingredients in number of medications used for the treatment

http://dx.doi.org/10.1016/j.saa.2015.01.036
1386-1425/Ó 2015 Elsevier B.V. All rights reserved.
 M.A. Mallah et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 141 (2015) 64–70
of flu and cold in children. It is similar in mode of action to aspirin,
hence is the most commonly used in pediatrics. It is surprisingly
safe and does not bear any risk of addiction [1–3].
The review of literature for the assessment of paracetamol
either individual or in combined dosage form reveals that a num-
ber of methods have been reported based on various analytical
techniques. Those established methods include titrimetry [4], flow
injection spectrophotometry [5,6], colorimetry [7], spectrofluori-
metry [8,9], chemiluminescence [10,11], high-performance liquid
chromatography [12–14], fluorescence detection after post column
enzymatic derivatization [15], gas chromatography–mass spec-
trometry [16], voltammetric method [17–19], flow injection and
capillary electrophoresis [20,21], terahertz spectroscopy using
PLS calibration model [22], micellar electrokinetic capillary chro-
matography [23], UV–Vis spectrophotometry [24–27], also some
electrochemical methods using modified electrodes have also been
developed for the determination of paracetamol [28–30]. Some of
the highly advanced and sensitive analytical techniques like
voltammetry, capillary electrophoresis are not frequently available
in pharmaceutical laboratories hence the choice for the analysis of
active pharmaceutical ingredients (API) becomes limited. As these
well established analytical methods usually offer high cost analysis
by consuming large volumes of solvents, long analysis time due to
lengthy and complicated sample preparation which makes them
unsuitable for rapid analysis, of bulk samples at industrial scale.
While using classical methods for the routine analysis sensitivity
and selectivity has always been an issue due to the significant
interference from the matrix. To counter these problems, the use
of buffers and costly derivatizing agents is a common practice for
the measurement of specific analyte; hence the need for the rapid,
sensitive, cost-effective and green method for the analysis of API
arises. The use of FTIR spectroscopy in pharmaceutical industry is
gaining much popularity as a quantitative tool due to its rapid
and non-destructive nature, simple sample preparation, ease of
use and less or no solvent consumption for monitoring quality
[31–35] as well as quantity of the raw materials and finished drug
products [36–39]. FTIR spectroscopy has been also a top choice for
minimizing the environmental issues regarding industrial chemi-
cal waste as it does not require much solvent. The structure of
paracetamol contains different functional groups including –N–H,
O–H, C@O and aromatic ring containing C@C. The band appearing
for C@O was selected for quantification as the interference arising
from excipients in pharmaceutical formulation is minimal in the
region.
The exclusive plan of this study aimed at developing a simpler,
inexpensive, rapid and environmental friendly method for quanti-
fication of paracetamol in solid formulations using transmission
FTIR spectroscopy in order to explore the potential and suitability
of FTIR for the use of API.
Experimental
Reagents and samples
Analytical grade paracetamol from Sigma Aldrich (Karachi,
Pakistan) was used in the present study. IR grade Potassium
Fig. 1. Chemical structure of paracetamol.
65
Bromide (KBr) for standard and sample pellets was obtained from
Sigma Aldrich. Some solid formulations containing paracetamol as
API (i.e. Calpol, Panadol extra, Disprol, Panadol CF, and Paraceta-
mol) were procured from local markets of Pakistan (Manufacturing
Date July/August 2011).
FT-IR calibrations
For the calibration purpose, a data set of 18 paracetamol
standards ranging from 0.005 mg to 1 mg paracetamol in KBr were
prepared to formulate uniform pellet of 100 mg weight each time.
In order to formulate homogenous pellets and get reproducible
results same pressure was applied. Then all the standards spectra
of various concentrations in the above mentioned range were ana-
lyzed in TQ Analyst program 7.3 (Thermo Electron) to develop
developing a calibration model using a straight line equation. Then
area under peak for all standard spectra was computed by selecting
specific region for the quantification of paracetamol in solid tablet
and capsules.
Sample preparation
Unlike other commonly employed methods, this method needs
simple sample preparation prior to FTIR spectra acquisition. The
only step involved is grinding of the exactly weighed solid pharma-
ceutical samples (tablet and capsules after removing coating) as
fine powder in agate mortar which reduces particle size of sample
for pellet.
Preparation of KBr pellets (with and without sample)
The uniform KBr pellets of 100 mg were prepared by taking
specific amount of paracetamol standard and oven-dried KBr to
ensure no residual water vapor. Then the mixture was condensed
in 13-mm die at a pressure equal to 5 tons till 5 min. Same proce-
dure was applied for the pharmaceutical samples also. 1 mg
sample was taken in 99 mg KBr for making sample pellet. Then
these pellets were scanned in Mid-Infrared region for recording
FTIR spectra.
FT-IR parameters for spectral acquisition
All IR spectra were recorded on 5700-FTIR spectrometer of
Thermo Nicolet with KBr accessory and deuterated triglycine
sulfate (DTGS) detector. This instrument was operated with OMNIC
(Thermo Nicolet) version 7.3. The resolution was optimized at
4 cm1 by averaging 32 scans in Mid IR region of 4000–400 cm1
and priority was not to lose any spectral information. The fresh
background spectrum was recorded from KBr pellet before each
FTIR run for standard and sample. All the spectra were recorded
in KBr pellet form under same optimized conditions.
Results and discussion
This new approach of analyzing API in pharmaceutical formula-
tions directly by applying transmission FTIR spectroscopy has a
number of advantages over already established lengthy and time
consuming procedures. The extraction procedures have been com-
pletely eliminated in order to achieve rapid, inexpensive and green
method. This not only minimizes the cost and time of the analysis
but the use of toxic chemicals has also been minimized.
In solid paracetamol formulation substances other than API are
used for various purposes they are called as excipients. The com-
monly used excipients for the formulation are lactose, magnesium
stearate, talcum powder, starch and avecil. These are added in
66 M.A. Mallah et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 141 (2015) 64–70
Fig. 2. Comparison of three spectra of 0.5 mg paracetamol standard, sample and mixture of excipients i.e. starch, magnesium stearate, lactose, avecil and talcum powder.
different ratios and vary from product to product. Fig. 2 shows
comparison of three spectra i.e. of paracetamol standard, paracet-
amol sample and mixture of excipients. From comparison it is clear
that standard and sample spectra easily stretch over the surface of
each other so there seems no significant interference caused by the
other matrix components which establishes that method is practi-
cal without carrying out extraction.
Selection of FTIR region for calibration model
Fig. 3 shows transmission FTIR spectra of the pure paracetamol
drug which is used as an API in pharmaceutical formulations and
treated as standard for the calibration purpose. Spectra contain
several prominent bands which all belong to the same component
hence instead of selecting a single band different regions were
tested to fit a linear calibration model for accurate results. In this
study both univariate as well as multivariate models are applied
in order to achieve linear regression and to evaluate the accuracy
and precision of the calibration set in the region 1800–750 cm1
with two point baseline. This was done to monitor response of
these two models for quantification of desired analyte in different
regions.
Fig. 3. FT-IR spectra of paracetamol standards.
Simple Beer’s law calibration model
Table 1 shows the response of the univariate simple Beer’s law
calibration model in different regions of the spectra by applying
different measurement criteria like peak height, peak area, baseline
correction either with two points or without baseline correction.
The results with peak height and peak area are comparable to
each other and are acceptable to same extent. The different regions
containing almost all the prominent bands were selected and
tested in TQ Analyst. The region 1800–1000 cm1 with two point
baseline correction and peak area was found to be the best region
for the accurate and precise recovery of up to 99.96% by using sim-
ple Beer’s law model having linear regression (R2) 0.9994 as given
in Fig. 4.
PLS calibration model
Another popular multivariate model is PLS. The region of
1800–1000 cm1 already tested in simple Beer’s law with two
point baseline and peak area measurement was selected in PLS
for generation of calibration from FTIR spectra of paracetamol
standards for quantification (Fig. 5).
 M.A. Mallah et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 141 (2015) 64–70 67

Table 1
Selection of FTIR region for application of simple Beer’s law calibration model.

Region selected (cm1) Measurement mode Baseline criteria (cm1) Regression line (a) Correlation coefficient (b) Recovery (%)
750–850 Peak area 750–850 16.3x + 0.34 0.9862 96.12
750–850 Peak area None 0.001x + 0.02 0.9783 94.79
750–850 Peak height 750–850 0.87x + 0.001 0.9832 97.05
750–850 Peak height None 0.789x + 0.00 0.9935 93.74
1190–1280 Peak area 1190–1280 12.27x + 0.057 0.9918 97.55
1190–1280 Peak area None 27.35x + 0.081 0.9896 96.72
1190–1280 Peak height 1190–1280 0.323x + 0.00 0.9983 96.98
1190–1280 Peak height None 0.475x + 0.87 0.9977 95.95
1402–1605 Peak area 1402–1605 3.43x + 0.04 0.9992 95.03
1402–1605 Peak area None 8.34x + 0.00 0.9985 93.06
1402–1605 Peak height 1402–1605 0.27x+.406 0.9987 97.42
1402–1605 Peak height None 3.87 + 0.00 0.9975 92.11
1610–1750 Peak area 1610–1750 42.2x + 0.00 0.9983 98.12
1610–1750 Peak area None 0.0001x + 0.00 0.9983 93.98
1610–1750 Peak height 1610–1750 0.432x + 0.00 0.9970 96.37
1610–1750 Peak height None 0.578x + 0.00 0.9981 94.76
1000–1800 Peak area 1000–1800 42.2x + 0.00 0.9994 99.96
1000–1800 Peak area None 0.0001x + 0.00 0.9983 97.82
1000–1800 Peak height 1000–1800 0.432x + 0.00 0.9980 98.07
1000–1800 Peak height None 0.578x + 0.00 0.9981 97.62

Fig. 4. Calibration curve for paracetamol in range of 1800–1000 cm1 using simple Beer’s law model.

The excellent calibration curve with (R2) 0.9999 as shown in
Fig. 6 was accomplished. The regression equation obtained from
the calibration data set was subsequently applied for quantifica-
tion of paracetamol concentration in pharmaceutical samples. As
the real sample also contains ingredients other than the analyte
so PLS is preferred quantitative model being multivariate as it
accurately states the spectral information from multi-component
analyte. The results through PLS are reliable and accurate when
spectral information is to be drawn through multiple bands in a
particular region with minimal spectral interference. The % differ-
ence plot as given in Fig. 6 indicates that variation between the
actual and calculated concentration values is small and there is
no significant difference between them. This exhibits sensitivity
of the method even at very low concentrations. The efficiency of
the chemometric model was analyzed through calculation of dif-
ferent errors i.e. and residual mean standard error of prediction
(RMSEP) and residual mean standard error of calibration (RMSEC)
were found to be 0.025 and 0.00104.
Analysis of pharmaceutical samples
The proposed method using FTIR spectroscopy assisted with
multivariate chemometric model was applied for the analysis of
solid pharmaceutical samples. Table 2 presents the results for
quantification of paracetamol. The determined concentration was
found to be in the range of 96–101% and was fully matched with
the labeled contents and is within the acceptable efficacy value
of 90–108%. The results were accurate according to permissible
68 M.A. Mallah et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 141 (2015) 64–70

Fig. 5. FTIR region (1800–1000 cm1) carrying most of the bands for paracetamol.

Fig. 6. PLS Calibration curve and % difference plot for paracetamol in range of 1800–1000 cm1.

limits of the pharmacopoeia in analyzed samples. The samples
were analyzed in quadruplicate and the standard deviation values
were also low i.e. 0.09–0.34. The method proved to be practical.
Method validation
The method validation was performed using standard addition
method by adding known amount of pure drug to one selected for-
mulation sample. Recovery of the exogenous amount added was
calculated to evaluate further accuracy of the method. The recov-
ery was calculated by the following equation:
Recovery ð%Þ ¼ ðX  Y=ZÞ  100
where, Recovery means paracetamol recovered (%), (Y) expresses
normal concentration of sample before addition, (X) is concentra-
tion of sample after addition of paracetamol after addition and (Z)
indicates added amount of paracetamol.
The statistical result for paracetamol recovery as given in
(Table 3) for a selected sample showed very good recovery of
98.85%, 99.44% and 99.96% with standard deviation of 0.29%,
0.21% and 0.35% using new analytical method. The results of this
method were compared with the reported method [40] and were
found to be comparatively better and reproducible. According to
United States pharmacopoeia satisfactory recovery is 90–108%
[41]. Hence the proposed method was found to be practical with
remarkable sensitivity.
The data reveals that mean recovery by applying this method
was found much higher with low standard deviation values which
indicated the high accuracy of the results. The correlation coeffi-
cient is also very good i.e. near to unity. The data was furthermore
 M.A. Mallah et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 141 (2015) 64–70 69

Table 2 reproducible as compared to univariate method in terms of high

Results for the paracetamol in pharmaceutical samples (n = 4). mean recovery, low standard deviation and high correlation coeffi-
Sample Paracetamol labeled Paracetamol cient values.
(mg/tablet) found ± SD (mg/tablet)
Sample 01 225 227.18 ± 0.31 Qualitative analysis with hierarchical cluster analysis (HCA)
Sample 02 225 229.05 ± 0.23
Sample 03 225 226.43 ± 0.31
Sample 04 225 223.82 ± 0.09
For qualitative analysis of the standard and sample spectra HCA
Sample 05 225 226.06 ± 0.36 was performed in order to measure the level of similarity by apply-
Sample 06 225 225.86 ± 0.19 ing numerical relationship Euclidian distance with ward type link-
Sample 07 225 228.45 ± 0.26 age from the absorbance values of the samples at the selected
Sample 08 225 227.57 ± 0.34
range of 1800–1000 cm1. Fig. 7 shows the dendrogram generated
with sample and standard spectra and it clearly separates sample
and standards from one another as sample also contains excipients
as well. This is due to the discrimination power of the FTIR spec-
Table 3
Recovery from tablet samples after exogenous addition of known amount of troscopy. The similarity index between sample and standard in
standards (n = 4). the particular region is over 99% which clearly indicates that the
interference from the matrix is non-significant hence the direct
Sample conc. Amount added Found Recovery (%)
(mg) (mg) (mg)a ± SD quantification of the paracetamol is possible even from the sample
This Reference
without any sample treatment.
work method [40]
226 10 235.68 ± 0.29 98.85 100.00
226 20 244.75 ± 0.21 99.44 99.95 Interference study
226 50 275.92 ± 0.35 99.97 99.96
a
In order to check the effect of the excipients; pure drug and
Values are mean of four determinations.
pharmaceutical sample were analyzed in comparison with mixture
of excipients on FTIR. Then the mixture of excipients was added to
pure drug and scanned similarly. There was negligible effect on the
Table 4
concentration of the analyte as it is evident from Fig. 2 hence elim-
Statistical figures of merit for the proposed method validation.
ination of extraction step did not imparted any significant interfer-
Parameter Univariate method (Beer’s Multivariate method ence from matrix components.
Law) (PLS)
Mean recovery (%)a 99.52 99.92
Limit of detection (LoD) and limit of quantification (LoQ)
Standard deviation 0.353 0.348
(SD)
Correlation 0.9994 0.9999 The calculation of LoD for newly developed method was done
coefficient by applying the formula given below:
t-Test (2.306)b 1.427 0.475
a
LoD ¼ 3  Sd  X=A
Average of four determinations.
b
Tabulated t-value at 95% confidence level and eight degrees of freedom.
where Sd stands for the standard deviation; X indicates concentra-
tion of analyte, while A is peak area.
LoQ was calculated similarly by using following formula:

LoQ ¼ 10  Sd  X=A:

Therefore, LoD and LoQ calculated for this method were

0.005 mg g1 and 0.018 mg g1 respectively. These results obvi-
ously indicate enough sensitivity of FTIR spectroscopic method in
transmission mode.

Conclusion

The present study described development of green, sensitive

Fig. 7. Dendrogram for classification of standard and sample using Euclidian
distance after HCA analysis.
and rapid method for accurate quantification of paracetamol in
pure drug and solid formulations i.e. tablets and capsules using
transmission FTIR spectroscopy. Analytical performance of this
method is found to be better than the previously reported meth-
ods. This method can be frequently carried out as it has made
the procedure of analysis simple by eliminating the complex step
of extraction. This method seems to have the potential to replace
the existing laborious and expensive methods for the analysis of
paracetamol.

tested by applying student t-Test at 95% confidence level as shown Acknowledgement

in Table 4. The calculated t-value was less than the tabulated value
hence there exists no significant difference between the population Authors gratefully acknowledge Pakistan Science Foundation
means of the results. The results by applying multivariate for providing financial support under project No. PSF/Res/S-SU/
chemometric (PLS) model were found to be more accurate and Chem/441 and NCEAC, University of Sindh Jamshoro, Pakistan for
70 M.A. Mallah et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 141 (2015) 64–70
providing all necessary facilities which made this research work
possible.
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