13th
INTERNATIONAL
CHEMICAL AND BIOLOGICAL
ENGINEERING CONFERENCE
Par
2018
BOOK OF
EXTENDED ABSTRACTS
Title
13th International Chemical and Biological Engineering Conference (CHEMPOR 2018)
Book of Extended Ab
s
tracts
Edit!.lrs
Joao Araujo Pereira Coutinho
Carlos Manuel Silva
lnes
Portugal
Ana Barros
-
Tinunons
Anabela Aguiar
Valente
Dmitry
Vic
t
orov
it
c
h
Evtyugin
M
ara Guadalupe Fre
i
re
P
ed
r
o
J
o
r
ge Carva
lh
o
Publisher
UA Editora
Universidade de
Aveiro
pt
Edition- October
20
18
ISBN
978~972~789~566~3CHEMPOR 2018
[P-BS25]
Extraction and recovery of phenolic compounds from biomass residues using aqueous solutions of
ionic liquids,
E.LP. Faria, A
.
F C
ld
udio, J.A.P. C
o
utinho, A
.
Sil
ve
str
e,
M. G. Fr
e
ir
e
. . .
.
. . .
.
. . .
.
. . .
.
.
3
5
0
LP-BS26J
Oxidative polymerization of magnesium-based Jignosulphon
a
t
es
from acidic
E
ucal
y
ptu
s
glo
bul
us
sul
-fite pulping by laccase: preliminary results
,
S.
M
ag
ina
, A.B.-Timmons
,
D.
V. E
v
tuguin .
. . .
.
.
.
. . .
. .
.
35
1
[P-BS27]
Valorization of
Quercu
s
cerris
cork by
s
upercritical extraction with modified carbon dioxide a
s
green
and efficient solution in relation to the classiical extraction with organic solvents
,
P. G. Viei
ra,
M
.
M
.
R. D
e Melo,
A.
~en, M.M.
Q
.
S
imoes,
H.
P
emira,
I.
P
ortug
al
,
C.
M.
Silva . . .
.
. . . .
.
.
.
.
.
.
. . .
.
. . .
.
353
[P-BS281L
i
f
e
-cycle inv
e
ntory anal
y
si
s
o
f
microalga
e
-based biom
a
ss production
,
M
.
B
.
-
Vieira, M. Freitas,
T.
M
at
a,
A
. M
art
i
ns
,
N.
Ca
etano
. . .
. .
.
. . . .
.
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.
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.
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.
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.
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.
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.
. . .
. .
355
fP-BS291
Valorization of
Aurantioch
ytri
um sp.
microalgae through supercritical fluid extraction: optimization
of conditions, measurement and modeling of kinetic curves,
M.M
.
R.
D
e
M
e
l
o
,
M.
S
ap
at
i
nha
,
J.P
i
-nh
eiro,
M. L
e
m
os
,
N.
M. Ban
dar
r
a,
I. Bat
ista, M.
C.
P
a
u
lo
,
J.
Co
ut
i
nh
o,
J.
Sa
r
aiv
a,
C
.
M.
Sil
va .
.
.
. .
. . .
3
5
7
[P-BS30]Pa
s
t and future research programme on biorefinery and bioproducts at the Navigator Compan
y
,
P.
P
int
o,
A.
G
asp
a
r,
R. R
odr
i
g
u
e
s
, C. Ne
t
o
. . .
.
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.
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. . .
3
5
9
[P-RSOl]
Removal of antimon
y
from water b
y
iron-coated eork granulates
,
A.
P
i
nt
or;
B
. V
i
eira,
R
.
B
oaven
t
ura
,
C.
Bote
lh
o . .
. . .
.
. . . ..
. . .
.
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.
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.
. . .
.
.
.
.
.
.
363
LP-RS02j
Study of the effect of the compensating anion on the C0
2
sorption cap
a
cit
y
of h
y
drotalcite-based
s
orbents
,
C.
R
ocha,
M.
Soria, L.M.
M
adeira
. . .
. . .
.
.
.
.
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.
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365
[P-RS031
Separation of nado1ol racemates by high pH reversed-phase preparative fixed-bed chromatograph
y
:
C
omparison of
C
18 Mat
e
rial
s
,
R
.S. Arafah, A
. R
ib
e
ir
o,
A.
E.
R
od
r
ig
u
es,
L.
Pa
is
.
.
. .
. .
. . .
.
. .
. .
.
. . . .
367
[P-RS04]
Solketal production from gl
y
cerol ketalization with acetone: Thermod
y
namic and Reaction Kinetic
Study
,
M
.
M
oreira,
R
. F
a
ria
, A
.
M
.
R
ibl!iro,
A
.E.
Rodrig
u
e
s
.
.
.
..
.
...
.
...
.
..
.
..
..
.
...
.
'l,.;:oJV~
CHEMPOR 2018
Sepa
r
ation of nado
l
ol racemates
by
h
ig
h
pH reversed-phase preparativ
e
fixed-bed
chromatography:
C
ompari
s
on
o
f
C18
materia
l
s
R. Arafah1•2, A. Ribeirol.2, A. Rodrigues1, L. Pais,
u.'
1Cenlro de lnve.1·tigurjio de i\fontanha (CJMOj, PoZvtedmic lnsl.ii7Jte of nraganffJ., Campus de .'Ymta Apol1lnia, Apartado I 134,
5301-857 Bragam;a, l'ortuga/; 2Laboratot:v q{Separation and Reactiont:ngineering, Famlty qf Engineering, University qf l'orto,
Rua Dr. Roberto Frias sin, 4200-465 Porta, Po11uga/.
*
pais@ipb.pt H!
!
¥f
~ 1400 1200>
.a
1000•
800r.
"'
~ 600 400 200 0 20 40 60 tlmotmln) M.,•lS mln 80 100 120Fixed-Bed technology will be used for the multicomponent
preparative separation of a pharmaceutical beta-blocker chiral drug.
New strategies using different achiral stationary phases will be
presented. Nadolol is a quaternary mixture of equal amounts of four
stereoisomers and will be used as case-study. A new methodology
for the design, optimization and experimental implementation of the
multicompommt separation will he introduced, including the use of
three different achiral adsorbcnts, the screening and choice of the best adsorh~t-solvent combination, taking in ac.count the final
preparative separation using the fixed-bed technology. Extensive
experimental and simulation resulls will be presented, including
solvent screening, measurement of equilibrium adsorption isotherms,
breakthrough measurements, and ftxed-bed (Azura prep HPLC unit)
experimental preparative separation using Cl8 columns under
reversed-phase mode.
Introduction
One of the main goals of the pharmaceutical indusny
nowadays, is to have more salt: and enici~l drugs. The purification of chiral phannaceutical drugs is getting the interest from the industrial companies, particularly after the international regulations. Currently, more than 40% of marketed drugs have cltiral active ingredients and almost half
oflhese drugs are marked as mcemic mixture.
Nadolol is one representative beta-blocker phrumaeeutical drug prescribed worldwide for relieve of several diseases mainly related with the cardiovascular system. However, like other
pharmaceutical drugs, it is also related with some severe risks,
such as depression, insomnia and cardiovascular failure, among
others. Some authors refer that these side effects could be
related to the L'lct that nadolol drug is still marketed as a
mixture of equal amounts of its fimr slereoisomers.
Additionally, there arc srudics referring that some therapeutic
effects of this drug arc related to only one of the four stereoisomers. Despite the growing pressure of the international regulation agencies for pharmaceutical drugs'
safety. pure single nadoJoJ stereoisomers are still 11c
commercially available.
The nadolol pharmaceutical drug represents a very interesting case-study or multicomponent chiral separation since it is
composed by four stereoisomers, being two pairs of enantiomers. In this way, it introduces the possibility of alternative strategies, using different kind of sepruation
sequences and techniques, the use of different packings (chiral
and achiral stationary phases), and the correspond~[ mobile phase opti1nization at both nonnal and reversed phase modes [ 1-3].
The design of the complete separation of nadolol slereoisomers
asks for a global experimental and simulation methodology considering both the characterization and the optimization of
eacl1 separation step and it-s sequences, to achieve the four na.dolol components pure.
1he present work will scope on optirnizing the enantiomers separation of nadolol using different achiral Cl8 adsorbcnts.
for this case, an extensive set of experiments were carried out
using achiral Cl H columns, such as, XBridge, Shield and
XSelect, all the three achiral adsnrbents obtained from Waters. 1he experimental work focus on screening of mobile phase composition, solubility ofnadolol racemates using dillerent
pure solvents and solvent mixtures. pulses under analytical and preparative conditions, equilibrium adsorption isotherms and breakthrough measurements. Additionally, experimental results
will include the preparative separation by fixed-bed
chromatography using an Azura Prep LC unit equipped with two 250 mUmi.npump heads and a XBridgePrcp OBD Cl8 10 J.lm (250x30 mm) column with a 10 J.lm particle si~.e diameter [2]. Experimental results presented in this work will stress the
advantage of u.~ing an intermediate step ba~ed on achiral
reversed-phase liquid cluomatography to perfonn the
separation of the two racemates ofnadolol.
Matet·ials and methods
TI1e mixture of the four nadolol stereoisomers was obtained
fro!!! Sig!lli!-A!drir.h (Sd•..n~!!dorf, G~!Tilllny). Th!.' HPLC-grad!.'
solvents, ethanol, acetonitrile and the basic modifier diethylamine (DEA) were obtained from Fluka (Bunchs,
Switzerland). lhree types of analytical (4.6rmn lD x 250rmn L;
particle size diameter of 5 )J.m) and preparative ( 19mm ID x
lOOmm L; particle size diameter of 10 !\Ill) Waters Cl8 achiral co!Uilllls were used: XBridge, Shield and XSclcct, all obtained
from Waters. The columns' eflici~cy characterization,
screening of the mobile-phase composition, loading
experiments, adsorption isotherms and breakthroughs
measurements were canied out using a prepi!Tiltive Knauer
HPLC system equipped with a Smartline UV detector 2520 set
at 270 nm wavelength, two Smartline 1050 pumps with SO mL
pump heads, a manual injection valve and two different loops
(I 00 and 1000 ~tL). The analytical pulses of nadolol were carried out on a Knauer analytical HPLC system. This system
was equipped with a Smartline UV detector 2520 set at 270 nm
wavelength, one Smart line I 050 pump with I 0 mL pump head, a manual injection valve and a loop of20 ~tL. The preparative separation of nadolol stereoisomers was carried out on an
Azura Fixed-Bed preparative HPLC system from Knauer (See
C
H
EMPOR 20
1
8
The system was equipped with twn preparative IIPLC pumps
J>2.1L model with 250 mUmin pump heads, and one UV/VlS
detector UVD2.1L model set at 270 nm wavelength. This preparative system was equipped with a Waters XBridge l'rep
C 18 cohunn of preparative diameters (30 mm ID x 250 mm L
and particle si~:e diameter of 10 J..lm). A llow-rate between 25 and 75 mT Jmin wa.~ used with this preparative column. Results
'lhe set of experimental and simulation results will include the
screening of the mobile phase composition using the tree types
uf' achiral ad~urbenl~. Se~eral re"ersoo-pha~e sohents based on
ethanol-water mixtures were tested in terms of resolution and
dispersion, by means of loading pulses. Results pn:sented will
include the experimental measurement of the equilibrium adsorption isotherms (Fig. 2) and breakthroughs experiments for all the three types of adsorbents and using the most promising solvent compositions.
20, -__ -__ -.:-=..._:-:-. :--:.,..::c,.:---:o,...., 15 ~
a
10..
...
- • etM141pHU ~~~ .a XS41htlpH11 4 1A, -- - - , ·~·· • .llll . . . l)lol11 - • aJIItU.,...,I .. ·- ... ~t41\mptt11 1_3c:·c
:
(giLlc:=c:
(g/L)figure 2. Comparison between experimental Wld modd results
for the adsmption equilibrium isothenns (left) and selectivity (right) for the two pairs of nadolol raccmatcs, as a function of
their feed concentrations, using 30%cthanolnO%watcr mobile
phase composition with 0.005% diethylamine (pH=ll) and the
three different C18 Waters columns: XBridgc (diamonds), Shield (circles) and XSelect (triangles). All littings use the
linear I Langnruir competitive model.
Acknowledgements
Modelling and its validation is a crucial step to the accurate
equilibrium and kinetic data estimation. Some simulation
results for the preparative separation of the nadolol racemates
by simulated moving bed technology will be also presented
(See Pig. 3). finally, some experimental results concerning the
preparative separation of nadolol racemates using the Azura Fixed-Bed preparative HPLC system will be also presented.
1.f ·:...._~ .. ,.~,.;..,,; ., ' ' •
j
···StlllldfiH1t o..a ~--xs.t~ptf11~
0.1~
... - ··-~~--~--~~--~10 o+o--~--~~s~~--~10 C,' (gll) C,' (g/L)Figure 3. SMB productivity (left) and solvent consumption (right) for the separation of nadolol racemates using the XBridgc (solid lines), Shield (dashed lines) and XSclcct
(dotted lines) c.olumns using a 30%ethanol/70%water with
0.005%dicthylaminc as mobile phase (pH-11) as a function of
the nudolol feed concentration. Conclusions
'lhe optimization of preparative fixed-bed chromatography depends on the proper choice of the mobile phase composition.
The separation of nadolol rucemales was studied ILo;ing
different ethanol/water compositions with thn:.c different achintl Cl8 Waters materials (Xfiridge, XSelect and Shield) at
both analytical and preparative scales. 'l11e design of the
preparative separation process was studied, by means of loading pulses, the measurement of the adsorption equilibrium
isotherms, breakthrough experiments using a 30%ethanol/70%water mobile phase composition.
A linear+Langmuir model was found to describe well the
adsorption behavior. Breakthrough experiments were also
perfonned to validate the equilibrium model and to predict
axial dispersion and mass transfer resistance. The equilibrium data was also used to predict the opentting c<mditions li1r future
extra simulated moving bed (SMB) operation.
Additional cxpcrin1cnts were carried out on a fixed-bed
preparative system in order to optimize the separation of
nadolol racemates. A mobile phase composition of
20%cthanol/80%watcr/O.l o/odicthylantinc was selected to perlimn a sequential live-injection experiment to conlirm the
viability of fixed-bed operation for obtaining pure nadolol
raccmatcs.
This work is a result of project "AIProcM1t@N2020 -Advanced Industrial Processes and Materials for a Sustainable Northern
Region of Portugal 2020", with the reference NORTE-01-0145-FEDER-000006, supported by Norte Portugal Regional Operational
Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund
(ERDF), and of project POCI-01-0145-FEDER-006984 - Associate Laboratory LSRE-LCM funded by ERDF through
COMPET£2020 - Programa Operacional Competitividade e lntemacionalizatyiio (POCI) - and by national funds through FCT
-Fundatyiio para a Ciencia e Tecnologia.
References
[I) R. Aralah, A. Riheiro, A. Rodrigues, T. Pais, XXJJ Tinct~ntm T ,uso-Galego de Quimica, fintgunya, Pmtugal, 2016. [2) R. Arafah, A. Riheiro, A. Rodrigues, L. Pais, I 0" Tincontro N11c. de Cromatogralia, firagan<;a, Portugal, 2017.
