Rgani Cmu Bayer Lecture 2013

Computer Aided Solvent Selection, Design
& Application
Rafiqul Gani
CAPEC, Department of Chemical & Biochemical
Engineering, Technical University of Denmark,
Lyngby, Denmark
rag@kt.dtu.dk
Some photos of Denmark!

DTU at Lyngby
Little mermaid
Nyhavn a
popular location
in Copenhagen
Hamlets castle
Bayer Lecture, Carnegie-Mellon University, 5 March 2013
Technical University of Denmark - Main Campus

DTU Chemical Engineering
Research at CAPEC
6 Research (Areas) Programs
CAPEC
List of CAPEC Co-workers : December 2012
Faculty Members & Administrative Secretary

(RaG, JA, GSI, JKH & EVA)
Researchers: 2
Lab Technicians: 0
PhD-students: 17* + 4
Head of CAPEC: RaG
Secretary: Eva; (Gitte)
MSc/BSc-students: 7+
Visitors/Guests: 3
Total: 39
* Including joint projects with PROCESS;
Per term
Computer aided solvent selection, design & application
Introduction
Solvents
Solvent: Solvent is that constituent of a solution that is
liquid in the pure state, is usually present in the larger
amount and has dissolved the other constituent (a solute)
of the solution. The solute may be a solid, a liquid or a gas.
The solvent may be a single compound or a mixture of
compounds.
Solvent applications
Reaction/Synthesis
Mixing: mass transport / phases
Selectivity
Reaction rate
Scalability
Isolation/Separation
Solvent extraction
Azeotropic distillation
Cooling crystallisation
Precipitation using an anti-solvent
Safety
exotherm control
Easier operation
Product Delivery
Paints, Inks, consumer products
(lotion, hair spray, ...)
Washing of solid product
Cleaning waste removal
Industrial sector usage tonnes per year

Paint manufacturers 79,376
Manufacture of organic base chemicals 74,163
Pharmaceutical industry 22,180
Metal coating industry 14,172
Construction 11,276
Graphic industry 8,624
Manufacture of wood articles (not furniture) 6,928
Manufacture of perfume and toilet articles 6,252
Manufacture of plastic articles 4,652
Food industry 3,717
Solvents (many are Volatile Organic Compounds, have

different uses in different industrial sectors)
Source: KemI's Products Register 2004
Examples of industrial usage & problem
Use of Solvents in Industry - Pharmaceutical

Water
Solvent and water
20%
contribute ~80% of the

process mass intensity.
Other
1%
20%
Reactants
Solvents
Emphasizes need for

research to reduce the
use & hazard of the
solvent; and improve
59% process efficiency
Gonzalez-Jimenez, GSK, 2007
Note: Contents of formulated (consumer) products are

also nearly 80% solvents
10
Motivation versus contradictions
Objective is to achieve zero solvent synthesis

(but is it possible without change of catalysts?)
Use green solvents (but the definition of what is
green is not clear!)
Make processes-products more sustainable (but
what is the solvent-separation-energy demand
versus sustainability analysis boundary?)
Ionic liquids have very low vapor pressures,
they can substitute organic solvents to reduce
the VOC problem (but many applications need the
solvent to vaporize out!)
11
Solvent selection and design problem

More than a million chemicals have been
identified and many more millions can be
generated through special software
How do we find the most appropriate

solvents (pure or blends) from them, for
specific applications?
12
Introduction
Problem definition & solution approach
13
The work-flow/data-flow for solubility calculation

AI or APIs
Do we have the
necessary
or Solvents
properties?
Yes
Yes
Do we have
values for i?
(Hf, Tm)
No
Databases
Databases
No
Model-based
properties
estimation
Choose a solubility
model
(UNIFAC, PC-
Do we have
pure-compounds
parameters?
SAFT, NRTL-SAC,
UNISAC)
Yes
No
Databases
Do we have
experimental
data?
No
Yes
Databases
Model-based
Pure-compounds
parameters estimation
Databases
Regression routine for

pure-compounds
parameters
Routine for Mixture

Model parameters
estimation
Databases
Databases
Routine for
phase-diagram
generation
Routine for
Activity coefficients
calculation
14
Mechanisms involved
Applications
Process design; product
recovery
Operation design;
equipments
Feasibility of synthesis
route ; process design
Reaction feasibility;
process design
Product design;
evaluate performance
Product process design
Problems
Mechanisms
Separation
LLE; SLE; VLE
Cleaning
Solids; liquids
Organic
synthesis
Inert; promote
reactions
Biphasic
reaction
systems
Create 2-phases
& promote
reactions
Formulated
products
Dissolve &
deliver AI
Pharmaceutical
products
Dissolve,
deliver, enhance
15
Mathematical (problem) definition

Fobj = min {CT S(Y, ) + f(x, y, u, d, ) + .........}
L1 1(Y, ) U1
L2 2(Y, , ) U2
L3 3(Y, , , x) U3
property function
models
L4 4(Y, , , y) U4
SL S(Y, ) SU
B x + CTY D
P = f(x, y, u, d, )
molecular/process
structural constraints
process function
models
16
Mathematical (problem) definition: Example

Design molecules that matches targets of Tb, T and
has vapor pressures at specified temperatures
L1 1(Y, ) U1
Tb = Yi i (ni, Ci)
L2 2(Y, , ) U2
T = [(Hv - RT)/Vm]0.5
L3 3(Y, , , x) U3
Log Ps = A + [B/(C + T)]
L4 4(Y, , , y) U4
SL S(Y, ) SU
B x + CTY D
P = f(x, y, u, d, )
17
Mathematical (problem) definition: Example

Design liquid blends that matches targets of Tm, density,
bubble point temperature at a specified pressure
L1 1(Y, ) U1
L2 2(Y, , ) U2
L3 3(Y, , , x) U3
L4 4(Y, , , y) U4
m = [(1/Vmi ) xi]
SL S(Y, ) SU
Tm = [(Tmi ) xi]
B x + CTY D
VLE; miscibility
P = f(x, y, u, d, )
18
Solution Strategy: Hybrid

L1 1(Y, ) U1
L2 2(Y, , ) U2
L3 3(Y, , , x) U3
L4 4(Y, , , y) U4
SL S(Y, ) SU
Stage IV
B x + CTY D
P = f(x, y, u, d, )
Stage IV: Min Fobj subject to 4
19
Another view of decomposition-hybrid" approach
Target
Where is Wally?
Donde esta Waldo?
Hvor er Holger?
........
Our target optimal

solution
........
20
A conceptual example
Solvent selection-substitution-design problem
Pre-design
Interpretation to
input/constraints
"I want acyclic

alcohols, ketones,
aldehydes and ethers
with solvent properties
similar to Benzene"
Design (Start)
A set of building blocks:

CH3, CH2, CH, C, OH,
CH3CO, CH2CO, CHO,
CH3O, CH2O, CH-O
+
A set of numerical
constraints
Design (Higher levels)

2.order
group
CH2
CH3
CH2
O
CH3
CH
CH3
CH3
Group from
other GCA
method
CH2
CH3
CH
O
CH3
CH2
A collection of group
vectors like:
3 CH3, 1 CH2, 1 CH,
1 CH2O
All group vectors
satisfy constraints
Start of Post-design
Refined property
estimation. Ability to
estimate additional
properties or use
alternative methods.
Rescreening against
constraints.
CH2
CH3
CH2
O
CH3
CH
CH3
CH3
CH2
CH3
CH
O
CH3
CH2
Method: CAMD (Computer Aided Molecular Design)

21
Introduction
Computer aided framework
22
Computer Aided Framework Main Features

Method & tool for generation of molecular
structures & blends
Method & tool for property estimation
Databases (data)
Property models
Property based function evaluations (eg,

VLE, LLE, SLE, ...)
Method & tool for screening of alternatives
Process-product performance models
23
Method & tool for generation of alternatives

Descriptors & Molecule Representation
Chemical Formula: CnH2n+2
Structural description:
CH3 - CH - CH2 - CH2 - CH3
|
CH3
Bonds: C-C, C-H, C=C,

Conjugates: Occurrences of different bonds
Groups: CH3 -, - CH2 -, - OH, CH3CO -,

24
Generation of alternatives
Groups as building blocks: CH3 -, - CH2 -, - OH,
CH3CO -, (a set of about 180 groups available)
Structural constraints
Size constraints
25
Predictive property models

GC MODELS
pure compounds
Compound 1
Compound 2
mixtures
Examples:
Examples:
VC 17.5 n j j
Joback
UNIFAC (VLE, LLE, SLE)
ln i ln i
COM
ln i
RES
Vc Vc 0 NiVc1i w M jVc2 j z OkVc3k

i
Marrero and Gani
Group contribution (GC) methods for property

prediction
26
Solvent Selection-Design Software

SolventPro
VLE
SLE
LLE
Methodology
Database
ProCAMD
ProCAMD
Solvent screening and solvent mixture

design for pharmaceutical applications
ProPred
Methodology
Models:
ESCAPE-23, 2012;
AIChE annual
meeting 2012
UNIFAC,
UNISAC, PCSAFT, NRTLSAC
Solvent database
IL (900)
Databases
ProCAMD
1500 solvents
27
Database: Knowledge Representation

Chemical Types
P1
Use of ontology
Example: Organic chemicals
Molecular Types
PP1,1
Example : Alcohols
Property Types
Example: Primary
Property variables
V1,1,1
Model Types
.
Pi
VT1
Normal melting point

u1,1,1,1
.
...
VTf,
ul,1,1,1
PPn1 , 1
...
Knowledge
base
....
Vk,1,1
Pm
Organic Chemicals
Solvents
Ionic Liquids
Lipids
Aroma
Active Ingredients
Critical temperature
....
PPj,1
Normal boiling point
At the end is a
frame with the
property value,
references,
uncertainty, etc
Vq1,1 ,1, 1
VTr
uac1,1,1,1, 1, 1
28
Property Model Library

Pure component (single value properties: Tb, Tc, Pc, ,
LC50, Tm, , .........) - 29 properties; GC+ models (+ 20)
Pure component (temperature dependent: pS, , Hvap,
, , .......) - 10 properties; PC-SAFT; correlations
Mixture properties (bulk properties: , H, , ....)
ideal mixing; PC-SAFT; special models
Mixture properties (phase equilibria: & ) - UNIFACCI; NRTL-sac; PC-SAFT; special models (UNISAC)
Solvent-process performance related properties

(solvent power, solvent loss, ....) property based models
Note: Property models need to be predictive and
qualitatively correct during generation & test
29
Modelling framework : Flexible, multiscale, reusable

How to perform
miracles in modelling?
Add one or more

parameters (regress
them with available
experimental data)
Or, use another model

to generate the
missing data
..
Develop a better theory!

30
Property Prediction : Flexible, multiscale, reusable
Property models at different scales

Correlations
Log Pi = Ai + [Bi/(Ci + T)]
Molecular
CH3-; -CH2-; -OH; ..
Zc = (Pc*Vc)/(83.14*Tc)
*Groups
C, H, O, N, S, .
* Use smaller scale models

to predict parameters for
the larger scale model
* Use same data sets
to develop models at
two adjacent levels
Tb = 222.543*log(Sum.Groups.I +
Sum.Groups.II + Sum.Groups.III)
P=niPi + b(v0) + 2c(v1)
*Atoms
Micro
Accuracy (verification)
Predictive power (design)
31
Modelling framework : Flexible, multiscale, reusable
Process models at various scales

Use smaller scale
model to predict
paramters/data for
larger scale model. Use
same data sets to
develop two adjascent
level models
Accuracy (verification)
Predictive power (design)
32
Computer aided modelling framework
Calculator
or solver
Robust & efficient solution strategy
Problem
definition
Human
System
characteristics
Problem
data
Model
construction
Tool
Model
solution
Model
calibration &
validation
Model
verification
Modelling tools: model reuse; model

aggregation/decomposition;
identification; analysis . (RodriguezMorales, 2009; Higtzig et a. 2009)
Model
object
Model library
Computer
Customized
simulator
CAPE-OPEN standards; plug & play
33
Introduction
Examples of application
34
Example of solvent-based separation

Products
Solvent
Process
Raw Materials
Clean Water
Extraction
Clean Water
Contaminated Water
Determine target for solvent
Solvent + solute
Problem solution
* fS = FW (Xin,s Xout,s)
* fS = 100 (0.018 0.00)
Solubility, S = fS/FS
Solubility, S. FS = 1.8
Solvent ID provides S
FS = S/1.8
Solvent ID decides extraction
process; solvent-solute relations
identify the process parameters
* Find solvent to match

target S use data & models
Order different solutions according
to cost of solvent & operation
35
Solvent Substitution: Benzene

Chemicals Design: Replacement of Benzene
We have an aqueous mixture of phenol

in a waste water stream. We need to
remove the phenol. Benzene is known as
a solvent but due to environmental
reasons, we cannot use it. What should
be a good replacement solvent for
benzene?
36

Step 1: Problem Formulation
* Property specifications:
Tb > 322 K
Tm < 314 K
29 kJ/mol < Hvap < 34 kJ/mol
logP > 1.5
High solvent power
High Phenol precipitation mole fraction
at 298 K
37

Step 2: Initial Search (generate
candidates through database search)
* Property specifications:
Tb > 322 K
Tm < 314 K
SP (solubility parameter)
* Use the above properties to search

among non-aromatic compounds
* Design acyclic compounds: alcohols,
ketones, aldehydes, ethers.
38
Step3a: Database search
Problem: Find solvents that have

19.5 > Sol Par < 20.5
Solution: Use a search engine within a database to
identify the set of feasible molecules
39
Step3b: CAMD
40
Step 4: Verification & Further Analysis

Methyl sec-Butyl Ether
2,2-Dimethyl-1-propanal
-3.863 kcal/mol
-7.081 kcal/mol
Structure
Solvation energy
COSMO solvation energy calculated using

MOPAC93
Indication that the aldehyde is a lower
ranking alternative (stripping operation).
41
Step 4: verification & Further analysis II

SLE Diagram for Phenol/Solvent system
320
300
Benzene (experimental Tfusion )
T (K)
280
260
Methyl sec-Butyl Ether (estimated T fusion )
Benzene (estimated Tfusion )
240
220
0.2
0.4
0.6
0.8
x(Phenol)
42
Example:Separation of an azeotropic mixture

Problem: A process stream of 50 mole% Acetone and 50
mole% Chloroform at 300K, is to be separated.
No external medium known
Separation techniques considered:
Binary ratios of properties
Adsorption (liquid, gas)
identify the following
Crystallization
alternatives
Desublimation
Distillation simple
Distillation extractive
Distillation with decanter
Liquid-liquid extraction
Flash/evaporation
Membrane (gas, liquid)
Microfiltration
Partial condensation
Separation techniques:
Distillation simple
Distillation extractive
Distillation azeotropic
Liquid extraction
Pressure swing
Note: Acetone-chloroform forms a high boiling azeotrope

that is pressure sensitive
43
Solvent design sub-problem
CAMD problem:
340 < Tboil < 420
Selectivity > 3.5
Solvent power > 2.0
No azeotropes
Solution:
1-Hexanal
Methyl-n-pentyl ether
(Benzene)
Number of compounds designed: 47792

Number of compounds selected: 53
Number of isomers designed: 528
Number of isomer selected: 23
Total time used to design: 57.01 s
44
Verification: Phase behaviour
45
Verification: Process simulation

Objective function:
Maximize
Profit = Earnings
Solvent cost
Energy costs
Constraints:
Acetone purity > 0.99
Chloroform purity > 0.98
Results:
Solvent
Solvent
flow rate
1-hexanal 0.082 kmol/hr
Reflux
Reb. 1
0.45
Reflux
Reb. 2
0.65
Objective
function
2860.51 $/hr
Computers & Chemical Engineering, 1999 (organic solvents), 2012 (ILs)

46
Product recovery/purification
Combine CAMD, ProPred, Solubility tools & Database
To solve following problems
Given, the molecular description of a pharmaceutical product,
find solvents needed a) in its production; b) in its formulation
Only problem a) to be highlighted
Solution strategy: Define CAMD problem to generate solvent
candidates; verify performance through solubility calculations;
check database to verify predictions
47
Solvent design: Sub-product & process design

Ibuprofen
Designed
solvent
SEM
(morphology
study)
Recrystallized
Ibuprofen
P-XRD
(Structure
Analysis)
T-X Diagram
333
Temperature (K)
328
323
Optimal Solvent
318
n- Hexane
313
Ethylene Glycol
308
303
298
1CH3, 2CH2, 1CH3COO, 1CH2O

2-EthoxyEthlyAcetate
0.2
0.4
0.6
0.8
Mole fraction of Ibuprofen (x1)
SLE diagram
A computer aided-molecular design framework for crystallization solvent design.
Karunanithi, A.T; Achenie, L.E.K; Gani, R. Chemical Engineering Science, 2006, 61, 1243-1256.
48
Product Recovery: Crystallization

Chemical product:
Ibuprofencooling as well as
Consider
drowning-out crystallization
Find solvents, anti-solvents & their mixture that satisfy the
following:
Potential recovery > 80%
Solubility parameter > 18 MPA1/2 (or > 30)
Hydrogen bonding solubility parameter > 9 MPA1/2 (or > 24)
Tm < 270 K; Tb > 400 K; -log (LC50) < 3.5
Solution strategy: Define CAMD problem to generate solvent
candidates; verify performance through solubility calculations;
check database to verify predictions
49

Chemical product:
Consider
50

Chemical product:
Consider
51
Formulation Design: Mixtures, blends, ...
Four case studies have been developed:

Design of a white paint for house interiors
Design of an alcohol based insect repellent (spray lotion)
Design of an water based insect repellent (spray lotion)
Design of a water resistant sunscreen (spray lotion)
AIChE J, 2011 (method), 2012 (verification)
52
Performance criteria:
what do consumers want?
Target properties:
which are the related chemical properties?
easy and fast applicability

high durability
good stability
water resistance
low toxicity
good material compatibility
pleasant skin feel
low price
form: viscosity , density , solubility

solvents evaporation rate T90
phase equilibrium: 1 phase system
solvents: oil soluble chemicals
lethal concentration LC50
suitable database of solvents
solvents with good cosmetic properties
cost C
53
Target properties:
Constraints:
viscosity
density ( V )
solubility
0.0
100.0
0.85AI
3.16
700
lethal concentration LC50

evaporation time T90
one phase system

solvent type
cost
<
<
V
<
< LC50
< T90
<
<
<
<
<
75.0
150.0
1.15AI
+
1300
cS
l/kmol
MPa
mol/m3
s
Considered later
in the design
54

Summary of all the actions performed
during the mixture design task:
Linear Design
4656
Non-linear Design
77
Stability Check
6
6
Verification
6
Optimal
55

Final result - optimal formulation:
Family
AIs
Solvent
mixture
Additives
Chemical
xi
wi
avobenzone
0.010
0.0325
octyl salicycate
0.013
0.0325
-Carotene
0.003
0.0163
-Carotene
0.003
0.0161
vitamin A
0.011
0.0325
TiO2
0.025
0.0325
methoxyacetaldehyde
0.789
0.593
2,2-dimethylpropylbutanoate
0.098
0.157
octorylene
0.009
0.034
parabens
0.021
0.033
iso-propyl salicylate
0.018
0.033
56
Solvents for Organic Synthesis

Given: A set of target (desired) properties
Find: Molecules and mixtures that match the
target properties
Example (solvents for organic synthesis): For a
specific reaction or reaction type, identify if solvents
are necessary to improve yield or promote the reaction.
If yes, find solvents that will have the least EHS impact
and improve reaction conditions.
Select from known candidates (database)

Design when candidates are not known
57
Application (organic synthesis) example - II

Glycerolysis reaction: Step 1 define problem
LIPASE
ENZYME
The objective is to find a

feasible set of chemicals
that could be used as
solvents in an enzymatic
glycerolysis reaction, which
takes place in the presence
of a catalyst (lipase
enzyme).
Collaboration with GSK &AstraZeneca
Introduction
Examples of application
New directions & conclusions
59
Role of solvents in Phase Transition Catalysis
Product
Starting material
R-Y + Q+X-
R-X + Q+Y-
Spent form of PTC
Active form of PTC

Organic solvent
Active form of PTC
M+X-
Q+Y-
Spent form of PTC
M+Y-
Final fate of displaced leaving group Y-
Q+X-
Source of desired anion

Aqueous phase
X = Cl; Y = Br; Q = TBA; R = benzyl-ring; M = Na

Known solvents: hexane, toluene; new: pentylacetate
Piccolo et al. CACE-31, 2012; ECCE-8, Berlin, 2011
60
Product-process design
Emulsified products & biphasic reaction systems
Kahlweits Fish diagram

(Kahlweit M. and Strey R.,
Angew. Chem. Int. Ed. Engl.
24 (1985) 654-668)
Fish diagram of the system

water-decane-2-butyloxyethanol
61
New solvents
Gibbs free energy of

mixing versus drug
volume fraction for
Soluplus-Felodipine
system at T = 140C
Modelling of solubility of
API in different lipids
62
Conclusions
It is important to understand the need for

solvents (when they are needed, what
functions they will have, ...)
Success of the method depends on data and
models (properties, process, ) employed
therefore, much effort has been made to
improve and extend the application range
Success with problems - biphasic reactions,
phase transition catalysts, API solubility - have
shown that the necessary models can be
developed even under limited data availability
What next? Add uncertainties in data & models
63
Current Industrial Consortium Members
30 member companies
Neste
Jacob Oy
US-EPA
WelcroHuntec
ChemProcess
Technologies
64

Rgani Cmu Bayer Lecture 2013

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Rgani Cmu Bayer Lecture 2013

Uploaded by

Copyright:

Available Formats

Computer Aided Solvent Selection, Design

Some photos of Denmark!

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Technical University of Denmark - Main Campus

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

6 Research (Areas) Programs

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Faculty Members & Administrative Secretary

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Computer aided solvent selection, design & application

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Washing of solid product

Cleaning waste removal

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Industrial sector usage tonnes per year

Solvents (many are Volatile Organic Compounds, have

Examples of industrial usage & problem

Use of Solvents in Industry - Pharmaceutical

contribute ~80% of the

Emphasizes need for

Note: Contents of formulated (consumer) products are

Motivation versus contradictions

Objective is to achieve zero solvent synthesis

Solvent selection and design problem

How do we find the most appropriate

Computer aided solvent selection, design & application

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

The work-flow/data-flow for solubility calculation

Regression routine for

Routine for Mixture

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

LLE; SLE; VLE

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Mathematical (problem) definition

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Mathematical (problem) definition: Example

Log Ps = A + [B/(C + T)]

Mathematical (problem) definition: Example

Solution Strategy: Hybrid

Another view of decomposition-hybrid" approach

Our target optimal

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

"I want acyclic

A set of building blocks:

Design (Higher levels)

Method: CAMD (Computer Aided Molecular Design)

Computer aided solvent selection, design & application

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Computer Aided Framework Main Features

Property based function evaluations (eg,

Method & tool for generation of alternatives

Bonds: C-C, C-H, C=C,

Groups: CH3 -, - CH2 -, - OH, CH3CO -,

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Predictive property models

UNIFAC (VLE, LLE, SLE)

Vc Vc 0 NiVc1i w M jVc2 j z OkVc3k

Marrero and Gani

Group contribution (GC) methods for property

Solvent Selection-Design Software

Solvent screening and solvent mixture

Bayer Lecture, Carnegie-Mellon University, 5 March 2013

Database: Knowledge Representation