Pietro Delogu [modalità compatibilità]

CONTINUOUS FLOW PROCESSES
A MULTIPRODUCT MODULAR
APPROACH
Pietro Delogu
P.Le Marinotti 1, 33050 Torviscosa (UD)

Mappa
Where Serichim is

Chemistry
Technology
Regulations
What Serichim does
New solutions for
our customers
“One Customer” Processes
Multiclient technologies:
continuous flow processes

“CONTINUOUS FLOW PROCESS “
Why it is important
• A “new” tool for European Chemical Industry
to maintain its competitivity
• An emerging technology with big impact on
the Fine Chemicals, Advanced Intermediates
and Pharmaceutical Active Ingredients
manufacturing

(reduced) Standard list of advantages usually claimed
in the literature for “flow chemistry”
Easy scale up
Low
environmental
impact
Safety
Process
intensification
Reliability

Our experience on “process intensification”
advantage: the Project Output
API Productivity improvement
obtained for the main
reaction
(Continuous/Batch)
Monthly required
capacity
Kg/month
Main reactor
volume
litres
Neuroleptic 40 a) 50000 200
Antiviral 90 b) 5800 50
Antidiabetic n.a. 3600 10
a) technology only based
b) chemistry and technology based
π
π
batch
1 ⎡ m ⎤
=
Sτ
⎢Vt
⎥
b ⎣ ⎦
S = dimensional
factor, l (of reactor)/g (of product)
τ =
continuous
batch time,
h
Fc c ⎡vm
m ⎤
= =
⎢
=
V τ ⎣tvv
vt ⎥
⎦
F = overallflowrate,
l/h
c =
V
τ =
=
product concentration,
g (of product)/l (of
reactor volume,
l
residence time, h
solution)

A common synthetic sequence
Solvent A
Quencher/
workup agent
preparation
Raw material
(solid)
Raw material
Dissolution
τ1
Quencher
Reagent/
solvent/
catalyst
Reaction
τ2
Quenching
τ3
Workup
wastes
Co-reagent
Co-reagent
preparation
Solvent B
Antisolvent
Batch
Crystallisation
τ4
Filtration
Drying
Product
Continuous
Mother
liquor
τ = τ + τ + τ +
b
1
τ = τ
2
2
3
( τ 4)

Co-reagent
Plant asset comparison
Batch PFD
Batch
Reactor
Filter
Continuous PFD

Batch
Batch-
Continuous-
Batch
Continuous
Scheduling options
ID Operation
1 Raw material dissolution
2 Co-reagent preparation
3 Reaction
4 Quenching & workup
5 Crystallisation
Lun 12 Set
12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 10
Equal productivity
for all equipments

Some conclusions on process
arrangements
• If we look only to the reaction we can get
misleading conclusions.
• Continuous mode has to be used for the
longest operation sequence as possible.
• As a rule, the continuous advantages are
higher when the reaction time is potentially
quite lower than the “service time”.
• Reaction chemistry and process engineering
have to be carried out at the same time!

The neuroleptic case
A + B
water
C + byproducts + 76.5 kcal/mole
Organic Inorganic Organic Inorganic
Half life time: from minutes to tens of minutes
depending on temperature and reagent concentrations
Batch time about 4 hours

Batch process PFD

Raw material
and solvent
Co-reagent
RE-100/A
Continuous process PFD
RE-100/B
PFR reactor 200 l
Quencher 1
CSTR 1
50 l
Quencher 2
Counterextraction
solvent
CSTR 2
50 l
L-L extractor
Aqueous butanol
Waste Treatment
Solvent
vessel
Batch Units
Continuous reactors
Continuous work up equipments
Process vessels
Evaporator
Crude
vessel

Where intensification was obtained
• In the reaction section intensification is a
consequence of better heat exchange of the
continuous reactor;
• In the extraction section the improvement is
due to the outstanding properties of liquidliquid
continuous countercurrent extraction.

Our proposal: a Multiproduct
Functional Unit

Scaling up of continuous reactors:
is it so simple?

Scaling up main parameters
• Batch reaction:
• Continuous reaction:
Batch reactor scaling up for
homogeneous reaction
Pilot scale
• Surface to volume ratio
• Surface to volume ratio
• Retention time distribution
Production scale

Pilot scale
S
V
Tubular reactor scaling up
2
= r = reactor
r
radius
Production scale
Vi
vi = vp
Vp
v = linear velocity
V
=
reactor volume
p = pilot
i = industrial production

Solutions to scale up problems:
numbering up
Really no scaling up!

T1
T2
Solutions to scale up problems:
T3
T4
T5
T6
CSTR cascade
P(θ)= fraction of feed having less than given
residence time
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Retention time integral distribution
for a series of n equal volume CSTRs
Number of CSTR
0.0
0 0.5 1 1.5 2 2.5 3 3.5 4
θ/τ= θ/τ=Residence θ/τ=
time/nominal residence time
1
2
4
6
8
10
12
14
16
18

Examples of RTD distributions of pilot
ηηSiemens
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Series of 10 CSTR
η⎠= 48 min, 10 Hz
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
F*t/V react = t/η
reactors
mS
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
Tubular reactor
0.0
16.4 8.00 17.0 2.24 17 .16.4 8 1 7.31. 12 17.45 .36 18.0 0.00 18. 14.24 18 .28.4 8
Ti me

We can use different PFRs, but we
have to reproduce or to improve RTD
Reactor discretization as
a bundle of ideal PFRs
μμμ μSiemens
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
E(t)
τ τ τ τ = 48 min, 10 Hz
0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
F*t/Vreact = t/ ττ ττ
θ

Fast evaluation of PFR performance
moles/initial moles
1.2
1
0.8
0.6
0.4
0.2
0
batch experiment
output
reagent clac
Intermediate calc
Product calc
reagent exp
intermediate exp
product exp
0 20 40 60 80 100 120 140
time, min
Reactor
discretisation
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
reactor
modeling
Expected
PFR outlet
composition
mS
PFR RTD
measure
0.00 20.00 40.00 60.00 80.00 100.00 120.00 140.00 160.00 180.00 200.00
Time, min

μS/Δμ Δμ ΔμS
1.1
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Sensitivity results
10 CSTR cascade
0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7
-0.1
θ
Raw material residual contents
CSTR cascade 0.13%
Static mixer 0.10%
Pure batch 0.07%
μS/Δμ Δμ ΔμS
1.1
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Tubular static mixer
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9
-0.1
θ

Conclusions
• Plug Flow Reactors are able to operate in conditions
forbidden for batch reactors;
• Scaling up has to observe some fundamental rules;
• Chemical development and reactor engineering can
not be carried out sequentially;
• “Pre-built” units can be of valuable help for a fast
and reliable continuous process development.