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M203 – Determination
of Aspirin and Caffeine in an Analgesic Preparation by NMR

Spectrometry

 

                          

 

 

 

 

 

 

Date of lab work:
18.01.2018                                                          
Date of report:  31.01.2018

 

 

 

 

 

 

 

Joanna Toporowska

K1600416

 

DATA AND RESULTS

 

Weight of empty flask – 9.1095
g

Mass of s-trioxane – 0.0503 g

Mass of tablet – 0.4322 g

Mass of half tablet – 0.2122 g

 

RMM of aspirin – 180 g/mol

RMM of caffeine – 194 g/mol

RMM of s-trioxane – 90 g/mol

 

 

 =

 

 =

 

 

 

 

 

 

Percentage of asp in tablet =

 

Percentage of asp in tablet =

 

 

Percentage of caffeine in
tablet =

 

Percentage of caffeine in tablet =

 

 

 

 

 

 

 

DISCUSSION

1.      Chemical
shift positions of the methyl groups in aspirin and caffeine.

 

Fig.1.
Structure of the aspirin.

As it’s seen above,
aspirin has one methyl group (Fig.1 – blue circle) with three equivalent
hydrogens that is attached to carbonyl group. As there are no hydrogens in the
close neighbourhood in the spectrum appears uncoupled singlet, at 2.3483. Expected
peak should be at 2.1 ppm, but it’s slightly higher which could happen because
of inductive deshielding from the oxygen side (ThermoFisher, 2017).

It can be also
seen very broad peak at 11.0658 which correspond to hydrogen in carboxyl group
(Fig.1. – purple circle), which shifts that singlet towards the left side. Usually
height of that signal is very low because it’s very wide, so the area of that
peak is the same as for the other protons appearing on the spectrum (ThermoFisher, 2017).

There are 4
hydrogens that are part of the benzene ring (Fig.1. – red circle) and they give
rise to the peaks in range between 7.1262 and 8.1313. They create the series of
multiplets. Doublets appear at 8.1075 – 8.1313 ppm and at 7.1262 – 7.1490 ppm.
Triplets appear at 7.3314 – 7.3726 ppm and 7.5987 – 7.6419 ppm. Multiplicity appear due to vicinal 3J and long-range
4J coupling of H+ around the ring. H1 and H3 are shifted downfield
because of the electron withdrawing (CO2H). H2 and H4 are shifted
upfield because of oxygen in acetoxy group that is electron-donating (ThermoFisher, 2017).

 

Fig.2.
Structure of the caffeine.

In the spectrum of
the caffeine can be seen 4 singlets due to 4 types of hydrogens that are in
different environment. The compound has 3 methyl groups. The first one (Fig.2.
– red circle) is attached to the nitrogen which is bonded to two carbonyl
groups, it gives rise to the signal at 3.9886. The second one (Fig.2. – blue circle)
is attached to nitrogen that is bonded to carbonyl group and one of the carbons
in ring. Signal appears at 3.5989. The last methyl group (Fig.2. – green
circle) is attached to nitrogen that is bonded to carbons that are part of the
ring. Because of the nitrogen that
are close to all the hydrogens deshielding can be observed. Mostly it can be
seen in the third peak because the position of hydrogens is near to a carbon
that is attached to a nitrogen (Shaikh Z., 2017). In the spectrum is also 1 hydrogen (Fig.2. – purple
circle) which is attached to the carbon that has in neighbourhood two nitrogen,
with one of them is double bonded. For that hydrogen signal rise at 7.2628.

 

2.Comparison of the results with contents claimed by
the manufacturer.

Information provided by manufacturer, Pfizer Consumer Healthcare (EMC, 2017):

Quantitative composition for Anadin Original –
tablets:

Active Ingredients:

Aspirin BP

325mg/tablet

Caffeine
PhEur

15mg/tablet

 

Results obtained
during this experiment are very close to the content claimed by manufacturer,
which can indicate that experiment was performed correctly.

Higher value for
aspirin can be result of measuring smaller integrals for main component (Thomson Eberhart S., Hatzis A., Rothchild R., 1986).

 

3. Factors affecting signal intensity.

–         
Relaxation
times, when the spectra become saturated (Saturation Effects) relaxation times
of protons are different and it can affect the strength of the signal (Reich H.
J., 2017). The signal intensity depends also on difference between two energy
levels. If the energy level is the same as the number of transitions, then
energy release and absorption will be 0 and it will be nothing to see on the
spectrum (Edwards J.C., 2017).

–         
Decoupling
– when it’s used then Nuclear Overhauser Effect occurs and can change the
intensity of the signals (Reich H. J., 2017)

–         
Acquisition
time – increasing this time will maximize the amount of signal (Reich H. J.,
2017),

–         
Temperature
can affect the duplicability of quantitative results. It should be constant
during the acquisition time. It can also affect the relaxation properties (Kumar Bharti S., Roy R., 2012)

–         
Gyromagnetic
ratio, it is a ratio of magnetic moment to its angular momentum. Its
proportional to signal strength. (Freude D., 2006)

–         
Nuclear
spin (Freude D., 2006)

–         
Measurement
time (Freude D., 2006)

–         
Density
of nuclei (Freude D., 2006)

–         
Strength
of external magnetic field, which is proportional to signal intensity (Freude
D., 2006) Shimming, which means homogeneity of the magnetic field should be
applied (Kumar Bharti S., Roy R., 2012)

–         
Receiver
Gain, can’t be either too high or low. It can cause loos of signal or
distortion (Kumar Bharti S., Roy R., 2012)

–         
correct
tuning and matching the frequency before the experiments should be done for all
samples as it can affect the signal intensity (Kumar Bharti S., Roy R., 2012)

–         
Signal
to noise ratio should be appropriate (Kumar Bharti S., Roy R., 2012)

–         
Electron
density

All these factors can
change the resolution, affect the peak shape, and cause even loos of signal.
Without good resolution, proper peak shape, baseline etc quantitative analysis
of the samples can’t be perform.

Signal to noise
ratio should be appropriate and time domain to provide precise quantitative
results (Kumar Bharti S., Roy R., 2012).

 

4. Comparison of NMR with UV and HPLC.

 

UV:

–         
Simple
and rapid, cheaper than HPLC as it doesn’t require expensive solvents (Eag.Laboratories, 2017),

–         
Non-invasive
(Geisler J., 2015)

–         
Can
reveal potential sample contaminants (Geisler J., 2015)

–         
Can
be used to determine the metal ions

–         
Higher
sensitivity and detection limit than NMR (Clark B.J., Frost T., Russell
M.A., 1993)

–         
Doesn’t
give enough information about the structure of the compound, thus it can’t be
identified completely (Clark B.J., Frost T., Russell
M.A., 1993)

–         
Short
time of analysis and small amount of sample required for experiment (Eag.Laboratories, 2017)

–         
Low
selectivity and sensitivity, it can be inadequate at low concentrations (Geisler
J., 2015)

–         
Widely
used for quantitative analysis (Clark B.J., Frost T., Russell
M.A., 1993)

–         
Other
components in the sample can cause the interferences (Eag.Laboratories, 2017)

–         
It
doesn’t work with compounds that don’t absorb light at that region (Geisler J.,
2015)

–         
One
of the disadvantages of that method are sample conditions, that can influence
the absorption. Such as pH, temperature or impurities (Geisler J., 2015)

 

 

 

HPLC:

–         
Separation
is rapid and can be repeated, also very efficient. Can be completed in 10-30
min with very high resolution and accuracy (Smith C., 2017)

–         
Preparation
of standard solutions required (Dong M.W., 2013)

–         
Complex
mixtures can be analysed using this method, it can be used to analyse
substances from small ions and organic molecules to big biomolecules and
polymers (Dong M.W., 2013)

–         
Column
can be used many times (Smith C.,
2017)

–         
Low
sensitivity for some of the compounds (Smith C., 2017)

–         
Can
separate mixtures and give the pure compounds (Dong M.W., 2013)

–         
Better
absorptivity onto stationary and mobile phase than UV (Dong M.W., 2013)

–         
No
dilution errors compare to UV (Smith C.,
2017)

–         
Can
be expensive as it requires a lot of different organic solvents (Smith C., 2017)

–         
Can
be used in qualitative
and quantitative analysis (Dong M.W., 2013)

NMR:

–         
Expensive
method (Banwell C. N., 1994)

–         
Samples
can’t contain any impurities before analysis (Emwas A.H., 2015)

–         
Very
high reproducibility (Emwas A.H., 2015)

–         
Can
distinguish even close related compounds better than UV or HPLC and thanks to
that specificity can be used to advantage in validation of methods for example
in chromatographic techniques (Holzgrabe U.,, Wawer I.,, Diehl
B., 2008)

–         
The
most suitable method to determine the structure of the compound (Banwell C. N.,
1994)

–         
Solid
samples, gas samples or tissues can be analysed by this technique, not just
liquid (Emwas A.H., 2015)

–         
Purity
of the compound can’t be determined but it can be by use of HPLC (Komoroski
E.M., Komoroski R. A., 2000)

–         
Non-destructive
method compared to HPLC (Emwas A.H., 2015)

–         
Requires
small sample volume (Komoroski E.M., Komoroski R. A., 2000)

–         
Little
or no sample pre-treatment (Komoroski E.M., Komoroski R. A., 2000)

–         
Can
be used to analyse the chemical and physical properties of the compounds, such
as electron density etc (Emwas A.H., 2015)

–         
In
quantitative NMR the main parameter that has an influence on signal is the type
of the solvent (Wawer I., Diehl B., 2017)

 

NMR
limitations:

–         
Quite
broad resonance that normally appears (Banwell C. N., 1994)

–         
High
detection limit that result in difficulties with trace detection (Komoroski
E.M., Komoroski R. A., 2000).

–         
Can
become complicated once the molecules will get bigger (Holzgrabe U., Wawer
I., Diehl
B., 2008)

–         
Samples
can’t contain any impurities before analysis (Holzgrabe U., Wawer
I., Diehl
B., 2008)

–         
Low
sensitivity, but it’s possible to improve it by increasing field strength or
dynamic nuclear polarization (Emwas A.H., 2015). Result of that it’s limitation
in quantitative applications (Holzgrabe U., Wawer
I., Diehl
B., 2008)

–         
In
NMR spectroscopy is just few parameters that can be changed to improve the
separation. In HPLC are many of them that can be optimized to achieve the best
separation, such as packing material in the column, particle size, modification
of the stationary phase etc. Also, composition of mobile phase can be various,
many options are possible to achieve the best results (Wawer I., Diehl B., 2017).

 

 

 

 

 

 

 

 

REFERENCES

Edwards J.C., 2017.
„Principles of NMR”. Process NMR
Associates LLC. Accessed, January 26, 2018.

http://www.process-nmr.com/nmr1.htm

 

Freude D., 2006.
“Spectroscopy”. Chapter NMR. Pp.13.

Reich H. J., 2017. “5-HMR-1
Integration of Proton NMR Spectra”. University
of Wisconsin. Accessed January 27, 2018.

https://www.chem.wisc.edu/areas/reich/nmr/05-hmr-01-integration.htm

 

Kumar Bharti S., Roy R., 2012.
“Quantitative 1H
NMR spectroscopy”. TrAC Trends in
Analytical Chemistry. Volume 35. Pp 5-26.

 

Jacobsen N.E., 2016. “NMR Data Interpretation Explained: Understanding 1D
and 2D NMR Spectra of Organic Compounds and Natural Products”. John Wiley & Sons. Pp 88-89.

Holzgrabe U., Wawer I., Diehl B., 2008. ” NMR Spectroscopy in
Drug Development and Analysis”. John Wiley & Sons. Pp 12-14.

Komoroski E.M.,
Komoroski R. A., 2000. „The Use of Nuclear Magnetic Resonance Spectroscopy in
the Detection of Drug Intoxication”. Journal of analytical toxicology
24(3):180-7.

 

Banwell C. N.,
1994. “Fundamentals of Molecular Spectroscopy”. Fourth Edition. England. McGraw-Hill Publishing Company.

Emwas A.H., 2015. “The
Strengths and Weaknesses of NMR Spectroscopy and Mass Spectrometry with
Particular Focus on Metabolomics Research”. Methods in molecular biology (Clifton, N.J.)
1277:161-193.

 

Wawer
I., Diehl B., 2017. “NMR
Spectroscopy in Pharmaceutical Analysis”. Elsevier.
Pp 145-146.

 

Smith
C., 2017. “Disadvantages &
Advantages of an HPLC”. Sciencing.org.
Accessed January 29, 2018.

https://sciencing.com/disadvantages-advantages-hplc-5911530.html

 

Eag.Laboratories,
2017. “Ultraviolet Visible Spectroscopy (UV-Vis)”. Eag.Laboratories. Accessed January 29, 2018.

https://www.eag.com/uv-vis-spectroscopy/

 

Clark
B.J., Frost
T., Russell M.A., 1993. “UV Spectroscopy: Techniques, instrumentation and data handling”. Springer Science & Business Media.

 

ThermoFisher, 2017. “NMR Spectrum of Aspirin”. ThermoFisher
Scientific. Accessed, January 30, 2018.

https://www.thermofisher.com/uk/en/home/industrial/spectroscopy-elemental-isotope-analysis/spectroscopy-elemental-isotope-analysis-learning-center/spectroscopy-elemental-isotope-analysis-resource-library/nmr-tech-talk/nmr-tech-talk-march-2015/nmr-spectrum-aspirin.html#

 

Shaikh Z., 2017. “Analysis of the H NMR of Caffeine”. Chem242.
Accessed, January 30, 2018.

https://chem242.wikispaces.com/Zahf%27s+analysis+of+the+H+NMR+of+Caffeine

 

Dong M.W., 2013. “The Essence of Modern HPLC: Advantages,
Limitations, Fundamentals, and Opportunities”. LCGC North America. Volume 31, Issue 6, pg 472–479.

 

Geisler J., 2015. “Choosing
the Best Detection Method: Absorbance vs. Fluorescence”. Eppendorf North America. Accessed January 30, 2018.

https://www.biocompare.com/Bench-Tips/173963-Choosing-the-Best-Detection-Method-Absorbance-vs-Fluorescence/

 

Thomson Eberhart
S., Hatzis A., Rothchild R., 1986. “Quantitative NMR assay for aspirin,
phenacetin, and caffeine mixtures with 1,3,5-trioxane as internal standard”. Journal of Pharmaceutical and Biomedical Analysis. Volume 4, pp. 147-154.

 

EMC, 2017. “Anadin Original”. Pfizer Consumer Healthcare. Accessed
January 31, 2018.

https://www.medicines.org.uk/emc/medicine/15592

 

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