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![Page 1: Coupling of spectroscopic, thermoanalytic and chemometric techniques for the resolution of enantiomeric mixtures Federico Marini, Remo Bucci, Ilaria Ginevro.](https://reader035.fdocuments.us/reader035/viewer/2022062322/5697c0071a28abf838cc6308/html5/thumbnails/1.jpg)
Coupling of spectroscopic, thermoanalytic and chemometric techniques for the resolution of
enantiomeric mixtures
Federico Marini, Remo Bucci, Ilaria Ginevro & Antonio MagrìDipartimento di Chimica, Università di Roma “La Sapienza”
![Page 2: Coupling of spectroscopic, thermoanalytic and chemometric techniques for the resolution of enantiomeric mixtures Federico Marini, Remo Bucci, Ilaria Ginevro.](https://reader035.fdocuments.us/reader035/viewer/2022062322/5697c0071a28abf838cc6308/html5/thumbnails/2.jpg)
ENANTIOMERS
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PAIN DRUG
ENANTIOMERIC MIXTURE
DIFFERENT PHARMACOKINETIC
BEHAVIOUR: study of the absorption process,
distribution, metabolism and excretion
DIFFERENT PHARMACODYNAMICAL BEHAVIOUR: study of the
mechanisms of action between the active principle
and the receptor
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ADVANTAGES IN THE USE OF THE ACTIVE ENANTIOMER ONLY
Half quantity of active principle
Elimination of the undesirable effects of the inactive form
Reduction of the metabolic burden on the liver
Reduction of the metabolic burden on the kidneys
Elimination of the intermediate products of the bio-inversion R→S
![Page 5: Coupling of spectroscopic, thermoanalytic and chemometric techniques for the resolution of enantiomeric mixtures Federico Marini, Remo Bucci, Ilaria Ginevro.](https://reader035.fdocuments.us/reader035/viewer/2022062322/5697c0071a28abf838cc6308/html5/thumbnails/5.jpg)
SINGLE ENANTIOMER DRUGS
d-ibuprofen (S)-citalopram
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KETOPROFEN
O
COOH
3HC H
(R)- 2- (3- benzoylphenyl)propanoic acid
O
COOH
H CH3
(S)- 2- (3- benzoylphenyl)propanoic acid
Analgesic
Non-steroidic anti-inflammatory
Antipyretic
![Page 7: Coupling of spectroscopic, thermoanalytic and chemometric techniques for the resolution of enantiomeric mixtures Federico Marini, Remo Bucci, Ilaria Ginevro.](https://reader035.fdocuments.us/reader035/viewer/2022062322/5697c0071a28abf838cc6308/html5/thumbnails/7.jpg)
RACEMIC KETOPROFEN
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d-KETOPROFEN
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KETOPROFEN (2)
• (S) is the active enantiomer (cyclooxigenase, which is the target enzyme is stereo-selective)
• (S) is not gastrolesive while (R) is• (S) doesn’t lead to the formation of ulcerae, while
(R) is ulcerogenic at the level of both intestines.
More pharmaceutical industries are moving towards the use of single enantiomers and therefore it is necessary to device a suitable way of determining enantiomeric excess
![Page 10: Coupling of spectroscopic, thermoanalytic and chemometric techniques for the resolution of enantiomeric mixtures Federico Marini, Remo Bucci, Ilaria Ginevro.](https://reader035.fdocuments.us/reader035/viewer/2022062322/5697c0071a28abf838cc6308/html5/thumbnails/10.jpg)
SCOPE OF THE WORK
Study of the possibility of devicing a rapid and cheap method to determine enantiomeric excess in
pharmaceutical preparation
DSC
Tf (racemate) = 95°C
Tf (enantiomer) = 78°C
IR
3500-2500 cm-1
1700-1300 cm-1
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DSC Analysis
• Particularly suited for the determination of purity of compounds (Van’t Hoff law)
• There can be deviations from linearity that need to be corrected.
• Some enantiomeric mixtures melt with decomposition so it’s difficult to estimate the melting temperatures (that are needed for the computation)
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EXPERIMENTAL DESIGN
• Check repeatability, reproducibility and effect of some experimental factors:– Way of preparing lab mixtures (directly in mortar
or by dissolution and riprecipitation)– DSC scan rate– Open/sealed capsula– Identity of mixtures prepared starting from the
single enantiomer plus the racemate and of those prepared mixing the two enantiomers
Preliminary study using mandelic acid
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OH
O
OH
(s)-mandelic acidOH
O
OH
(R)-mandelic acid
MANDELIC ACID
DSC
Tf (racemate) = 118°C
Tf (enantiomer) = 132°C
IR
3500-2500 cm-1
1700-1300 cm-1
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PHASE DIAGRAM
105
110
115
120
125
130
135
0 20 40 60 80 100
% (S)-mandelic acid
T (°C)
fmix
fen
en
T
1
T
1
R
H =ln x
f
fmix
frac
rac
T
1
T
1
R
H2 = x-14xln
f
Prigogine-Dufay Schroeder-Van Laar
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SOME CONSIDERATIONS
• No difference in preparing the mixtures by directly weighing and mixing in mortar or by dissolution and riprecipitation.
• No detectable effect of scan rate• No difference in mixing R+S or Rac+S• Sealed capsula provided better reproducibility• Presence of one eutectic
• It’s difficult to measure Tf close to the composition of the eutectic
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IR SPECTROSCOPY
500 1000 1500 2000 2500 3000 3500 4000
2
3
4
5
6
7
8
9
x 10-4
ni
A
racemate
(S)-mandelic
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PLS CALIBRATION
• 2 significant components (about 94% Y-variance explained)
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MCR
Better results with three component, probably due to background effects
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MCR (2)
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KETOPROFEN - PLS
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KETOPROFEN – MCR
0 10 20 30 40 50 60 70 80 90 1000
10
20
30
40
50
60
70
80
90
100
pred
icte
d en
antio
mer
ic e
xces
s
measured enantiomeric excess
MCR 3 components
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MCR(2)
500 1000 1500 2000 2500 3000 3500 40000
0.02
0.04
0.06
0.08
0.1
ni
A
MCR component
ketoprofen racemate
500 1000 1500 2000 2500 3000 3500 4000
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
ni
A
MCR component
(s)-ketoprofen
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CONCLUSIONS
• Coupling of IR spectroscopy and chemometrics seems to provide a rapid and cheap tool to determine enantiomeric excess to an acceptable accuracy
• Possibility of improving these results by variable selection (GA, iPLS_GA)
• Next step is the validation on real formulates
![Page 24: Coupling of spectroscopic, thermoanalytic and chemometric techniques for the resolution of enantiomeric mixtures Federico Marini, Remo Bucci, Ilaria Ginevro.](https://reader035.fdocuments.us/reader035/viewer/2022062322/5697c0071a28abf838cc6308/html5/thumbnails/24.jpg)
СПАСИБО!