Introduction to chemical product design

design,
molecular design problem definition & role of
property
t modelling
d lli

Rafiqul Gani
CAPEC
D
Department
t t off Chemical
Ch i l E Engineering
i i
Technical University of Denmark
DK-2800 Lyngby,
y g y Denmark
 Overview - 1
P bl
Problem Definition
D fi iti
Process Design Product Design

Raw Product Atoms or

material Process Products properties
Product molecules
Fl
Flowsheet?
h t? molecule/
mixture?
Operating Equipment
condition? parameters? Product Molecule or
functions? mixture
Product Application Design synthesis?

Product Performance
Application
process? Integrate Process-Product
Application Equipment & Application
conditions? parameters?

Workshop on Product Design, NTUA, March 2011 2

 Overview - 2
E
Examples
l off Product-Process
P d tP Integration
I t ti
Process Design Product Design

Raw Product Atoms or

material Process Products properties
Product molecules
Fl
Flowsheet?
h t? molecule/
mixture?
Operating Equipment
condition? parameters? Product Molecule or
functions? mixture
synthesis?

•Petroleum
P t l blends
bl d & petroleum
t l products
d t Routinely solved!

•Polymers & blends Can be solved!

Process role?
•Specialty chemicals (including drugs, ….)

Workshop on Product Design, NTUA, March 2011 3

 Overview - 3
E
Examples
l off Product-Process
P d tP Integration
I t ti
Product Design
For products
F d t such h as Atoms or
Product
drugs, pesticides, food, … properties
Product molecules
delivery and application is molecule/
important & needs to be mixture?
validated Product Molecule or
functions? mixture
Product Application Design synthesis?

Product Performance
Application
process? Production process
Application Equipment needs to be reliable – first
conditions? parameters? time right is important

Workshop on Product Design, NTUA, March 2011 4

Course Content
• Different types of design problems

•Modelling issues
pp
•Solution Approaches
• Concepts
• Single molecule design
• Mixture (blend) design

Workshop on Product Design, NTUA, March 2011 5

 Different Types of Design Problems
1 Design of Molecule and/or Mixture
1.

Given, a set of target properties , find molecules or

mixtures that match the target properties CAMD & CAMbD
solvents,
l t fluids,
fl id … d
drugs, pesticides,
ti id aroma, ….

Low Value High

L
Large Production rate Small
Easy Finding candidates Difficult

Workshop on Product Design, NTUA, March 2011 6

 Different Types of Design Problems
1 Design of Molecule and/or Mixture
1.
CAMD & CAMbD: Example
From a list of 250 solvents, find those that can be used as an oil-
paint additive characterized by 25%-, 50%- & 75%-evaporation
rate, solubility, viscosity and surface tension. Form the feasible
set, find the optimal cost solvent mixture.

• Sy
Synthesis
es s method
e od for
o mixtures
u es
• Property models for solvents
• Evaporation models for solvents
• Cost = f(Ci, xi)

Note: Mixture design similar to oil-blend (petroleum,

(petroleum
edible oil, ….), polymer blend, formulations, ….

Workshop on Product Design, NTUA, March 2011 7

 Different Types of Design Problems
1 Design of Molecule and/or Mixture
1.

Given, a set of target properties , find molecules or

mixtures that match the target properties CAMD & CAMbD
solvents,
l t fluids,
fl id … d
drugs, pesticides,
ti id aroma, ….

Issues & Needs

• Generate feasible candidates (synthesis method & tool)
• Estimate
E ti t target
t t properties
ti (predictive
( di ti property t models)
d l)
• Evaluate performance (application process models)
A h i ett al,
Achenie l Computer
C t Aided
Aid d M
Molecular
l l D Design:
i Th
Theory & Practice,
P ti CACE
CACE-12,
12 2003

Workshop on Product Design, NTUA, March 2011 8

 Different Types of Design Problems
2 Product
2. Product-Process
Process Evaluation
Given, a list of feasible candidates (product and/or process), the
objective
bj ti is i to
t identify/select
id tif / l t the
th mostt appropriate
i t product-process
d t
based on a set of performance criteria.
For product design,
design this problem is similar to CAMD but without the
generation step; also, similar to CAMbD where additives are added to
a product to significantly enhance the performance of the product
Examples
• Select the optimal combination of pesticide and
surfactants that match the needs of specific plants
• Select the optimal combination of drug/pesticide,
solvent and polymeric microcapsule for controlled
release of the product
• Increase the yield of a product by hybrid process
operation
Workshop on Product Design, NTUA, March 2011 9
 Different Types of Design Problems
2 Product
2. Product-Process
Process Evaluation
Simple Example: From the derivatives of Barbituric acid, identify the
candidate
did t that
th t is
i required
i d in
i the
th smallest
ll t amountt (C) tto produce
d a
1:1 complex with protein (binding to bovine serum albumin) –
calculated as a function of octanol-water partition coefficient of the
candidate compounds: Log10(1/C) = 0.58 log10P + 0.239
• Synthesis tool for isomer generation
• Property model for Log10P
• Verify solubility in water

Note: How is the backbone (barbituric acid) identified and how

is the relation (drug activity) between C vs log10P found?

Workshop on Product Design, NTUA, March 2011 10

 Different Types of Design Problems
2 Product
2. Product-Process
Process Evaluation
Process
Analytical
Technology
– PAT
To ensure
final product
p
quality!
Estimate
critical
iti l
scientific &
regulatory
parameters
A. S. Hussain,
early! CDER, FDA, 2002

Workshop on Product Design, NTUA, March 2011 11

 Different Types of Design Problems
3 Design of Product
3. Product-centric
centric Process
Problem Characteristics
• Products are consumer
Issues & Needs
products such as soap,
detergents, fragrances, food, Algorithm for generation of
skin-care
ki … process flowsheet
fl h t or
• Complex chemical systems batch recipe
involved
• Life of the product is getting Process-operation models for
shorter verification by simulation
• Volume/cost relationship p
needs to be improved by Property models for
selling more
product/process analysis
• Low-cost chemical routes are
needed (better catalysts,
faster reactions, increased
yields, …)

Workshop on Product Design, NTUA, March 2011 12

Framework for Integrated Approach - 1
Integration of Product-Product
Product Product Design

hwax

hcuticle

Workshop on Product Design, NTUA, March 2011 13

Role of property modelling

Prediction
P di ti and d measurementt off
properties for product design

Workshop on Product Design, NTUA, March 2011 14

 Motivation – I: Chemicals based products
Example-1: Design of a consumer product -
an insect repellent lotion
What does it involve? Determine a liquid
formualtion that is effective against
mosquito,
it hhas a pleasant
l t smell,
ll a good
d skin
ki
feeling and is a water-based product (active
ingredient water
ingredient, water, solvents
solvents, additives)
Properties?The above product attributes,
when translated,
translated means that target values
on the following properties need to be
matched: 90% evaporation
p time,, phase
p split,
p ,
solubility, viscosity, molar volume, toxicity,
etc., & cost

Workshop on Product Design, NTUA, March 2011 15

 Motivation – II: Chemical processes
E
Example-2:
l 2 Design
D i off a chemical
h i l process
What does it involve? Combine different unit operations
to convert raw materials (chemicals) to desired
products (chemicals) in a sustainable, efficient and cost
effective manner
manner.
Properties? Wide range of properties needed to
establish
t bli h the
th chemical
h i l product
d t (pure
( compound d and/or
d/
mixture properties) and the process (how the chemical
properties change under conditions of temperature,
pressure and/or composition). Monomer A

Separator
Monomer B effluent

Solvent (S)

Initiator (I)
MIXER

Transfer
agent (T)

Inhibitor (Z)
REACTOR

SEPARATOR

Copolymer
product

Workshop on Product Design, NTUA, March 2011 16

 Challenges & Issues
Wide range of products & processes must be handled

.....
Nutrition
Fertilizers Electronics Communications,
Entertainment
Chemical
Vitamins Processes Fuel
Mobility

Pharmaceuticals Plastics
DetergentsColorants and
Healthcare coatings

Clothing
Housing

Workshop on Product Design, NTUA, March 2011 17

 Challenges & Issues
How tto provide
H id the
th necessary property
t values
l in
i
a fast, efficient and reliable way?
Software
tools:
models; algorithms;
databases

Chemical Properties:
systems:
organic; polymers; pure compound
electrolytes; .. & mixture
i t

Workshop on Product Design, NTUA, March 2011 18

 Challenges & Issues
Properties for product-process design*
Databases: collection
of measured data
(there are gaps in the
database)

Property models: fill-

in the gaps (available
models are not perfect )

*Synthesis: generation-screening of alternatives (fast,

qualitatively correct predictive models are needed)

*Design/analysis: selection-validation (reliable, quantitatively

correct models are needed)

Workshop on Product Design, NTUA, March 2011 19

 Role of property models
Property models Log Pi = Ai + [Bi/(Ci + T)]
Property models
Monomer A

Separator
Process models are embedded into
process models
Monomer B effluent

Solvent (S)

Initiator (I)
MIXER

dm
 f in ,i  f o u t ,i  r ( m , T , P )V ; i  1 , N C
T
Transfer
f
agent (T)

Inhibitor (Z)
i
REACTOR

SEPARATOR
dt
Copolymer
product

Operation models
ntal

Formulation

su
or

ustaina
envirronmen

process

M
Models
Models fo

mpact

metrics
Process models model
Property-kinetics
im

Product

ability
s for
models
evaluation
Cost models model

Workshop on Product Design, NTUA, March 2011 20

 Property Modelling Concept

Predictive: Group contribution plus atom

connectivityy for p
primary
yppure component
p
properties and mixture properties (GE-models*,
viscosity,
y surface tension, EOS ((PC-SAFT)) ...))
Correlated: Secondary pure component
properties (Antoine
(Antoine, DIPPR
DIPPR-functions,
functions equations
of state, ....) and mixture properties (GE-models**,
viscosity surface tension
viscosity, tension, EOS (SRK
(SRK, PR)
PR), ...))
* UNIFAC ((different versions))

** NRTL, UNIQUAC, Wilson, ....

Workshop on Product Design, NTUA, March 2011 21

 Property Model Development – GC concept
Organic Chemical & Polymer Properties
1st-order: CH3 , CH2, CH, 3

OH, COOH, CH3CO, …. 5 1

2nd-order: (CH3)2CH,
CH .. 2 4

3rd-order: HOOC-(CHn)m- v
0 v
1 v
2
COOH (m>2, n in 0..2)
groups
g p connectivity
y index

REPRESENTING DATA SET AS GROUPS & ATOMS

EXPERIMENTAL DATA SET COLLECTION

Workshop on Product Design, NTUA, March 2011 22

 Property Model Development
Organic Chemical & Polymer Properties
DETERMINING ATOM or MINIMIZATION OF SUM OF
GROUP CONTRIBUTIONS SQUARED RESIDUALS
( experimental – estimated)

MARRERO
O / GANI
G GC-method
GC et od (2001)
( 00 ) Atom-CI
to C Model
ode (2006)
( 006)
f(y)=∑aiAi + b(vχ0) + 2c(vχ1) +
f(y) = ∑niCi + w∑mjDj + z∑okEk + F
2c(vχ2) + D

Note: f(y) is function of property x; example f(y) = Exp(Tb /tbo)

MODEL DEVELOPMENT

REPRESENTING DATA SET AS GROUPS & ATOMS

EXPERIMENTAL DATA SET COLLECTION

Workshop on Product Design, NTUA, March 2011 23

Property prediction (pure component)

Workshop on Product Design, NTUA, March 2011 24

Property prediction (pure component)

Workshop on Product Design, NTUA, March 2011 25

Property prediction (pure component)

Equations of
state: SRK,
PR, PC-
SAFT, ..
SAFT

Workshop on Product Design, NTUA, March 2011 26

 Property prediction: organic chemicals & polymers
Modelling options for primary properties
GC model + connectivity indices
Gcplus concept
Generation
G ti off
f (Y )   NiCi  f (Y )  higher order
*
missing groups for
i pure compound GC
models[1]

GC+ models
GC model +
Group contribution based experimental data
models

GC model (MG, CG, JR, W, …) GC model + force field (MM2)

Higher order models for
Gani, R.; Harper, P.M.; Hostrup, M. Automatic Creation of
structure distinction (cis-
Missing Groups through Connectivity Index for Pure-Component trans isomers)
Property Prediction.
Prediction Ind
Ind. Eng
Eng. Chem.
Chem Res.,
Res 2005,
2005 44,
44 7269
7269.

Workshop on Product Design, NTUA, March 2011 27

 GC+ concept for mixture property prediction

UNIFAC GC models

Compound 1 Compound 2
lni ln i
COM
lni lni
RES RES2

1. Given: Compounds, compositions & temp.

2. Represent molecules with 1st-order
1st order & 2nd-
2nd
order groups
3. Retrieve group parameters
4. Calculate activity coefficients in liquid
phase
5. .......

Equlibrium
q systems:
y VLE, LLE, SLE, VLLE, SLLE, SLVE

Workshop on Product Design, NTUA, March 2011 28

 The UNIFAC-CI Concept
Methodology to fill the blanks in the UNIFAC matrix

A lot of gaps in Sometimes time

VLE, SLE, LLE
th UNIFAC matrix!
the ti ! consuming and
experiments to
collect data expensive and
even not possible

Filling the UNIFAC

matrix jjust
By using just atom and
with the published
bond information
VLE, SLE and LLE
Of the groups
data
describingg the
GC model for Atom and bond molecules
Mixtures Based information
(UNIFAC) (connectivity indices) •Without any extra experimental data
•With reasonable accuracyy
UNIFAC-CI

Gonzales et al , Prediction of Missing UNIFAC Group-interaction, Parameters through connectivity

indices, AIChE J (2006); FPE (2010-submitted)

Workshop on Product Design, NTUA, March 2011 29

 Predict Missing UNIFAC Group Interaction Parameters
CH2
C=C
C≡C
ACH
ACCH2 C,O,H atoms (current state)
OH
CH30H adding N atoms
Potentially all the
ACOH
DOH adding F atoms group
g
H2O
CH2CO adding Cl atoms interactions
CHO
Furfural
CCOO
adding Br atoms parameters
HCOO
CH2O
adding I atoms
could be covered
COOH
CNH2
adding S atoms
using
CNH
(C)N3
adding Si atoms
UNIFAC-CI !
CCN adding Cl & F atoms
ACNH2
Pyridine
CNO2
ACNO2
DMF
ACRY
CF2
ACF
CCl
CCl2
CCl3
CCl4
ClCC
ACCl
Br
I
CS2
CH3SH
DMSO
COO
SiH2
SiO
NMP
CClF
CON
OCCOH
CH2S Workshop on Product Design, NTUA, March 2011 30
Morpholine
Thiophene
 Property prediction: UNIFAC-CI (VLE)

Methylcyclopentane- Ethanol-Hexane at 473 K

Benzene at 298 K

Workshop on Product Design, NTUA, March 2011 31

 Property prediction (mixture): UNIFAC-CI
Example: Generation of missing parameters for solubility
predictions of pharmaceutical active ingredients

Workshop on Product Design, NTUA, March 2011 32

Property prediction software
S it d ffor product-process
Suited d t d i /
design/analysis
l i

MoT

Introduce
new models
to the
system

Workshop on Product Design, NTUA, March 2011 33

 Database development
*K
Knowledge
l d representation
t ti (developed
(d l d ontology)
t l )
•Classes ((chemicals;; AIs;; Aromas;; Solvents;; ....))
•Sub-classes (organic, polymers, inorganic, ..)
•Instances
I t (alcohols,
( l h l ketones,
k t paraffins,
ffi ..))
•Objects-A
j (property
(p p y types:
yp primary,
p y, ...))
•Frames (property values: Tb, Tc, Tm, ...)
•Objects-B (applications: solvents, ....)
* Search engine
g for data-retrieval ((forward and/or
reverse)
R. Singh et al. ”Design of an efficient ontological knowledge based system for selection of
process monitoring and analysis tools”, ” C
Computers & CChemical Engineering, 2010

Workshop on Product Design, NTUA, March 2011 34

 Database: Contents & features

• Pure compound data: primary properties

• Binaryy mixture data: VLE and infinite dilution ((in
water)
• Solid solubility data (C4 – C60)
• Special databases
• Solvents
• Active ingredients
• Aroma
o a
• Agents (neutralizers, emulsifiers, ....)
• Search engines & data retrieval interface
Example of a lipid database and associated property models
(Diaz-Tovar
(Diaz Tovar et al
al., FPE
FPE, 2010)

Workshop on Product Design, NTUA, March 2011 35

 Hierarchy of property models
U a more predictive
Use di ti model
d l tto predict
di t th
the missing
i i parameter
t
Correlations Pi = Ai + [Bi/(Ci + T)]

Molecular Zc = (Pc*Vc)/(83.14*Tc)

CH3-; -CH2-; -OH; ….. Tb = 222.543*log(Sum.Groups.I +

Groups Sum.Groups.II + Sum.Groups.III)

C, H, O, N, S, ….
Atoms P=∑niPi + b(vχ0) + 2c(vχ1)
Use the smaller scale (atoms)
model to predict the missing
parameters of the larger scale (GC) Micro
Accuracy (verification)

Predictive power (design)

Workshop on Product Design, NTUA, March 2011 36

 Increasing application range of property models
Accuracy
y (q
(quantitative))
Pi = Ai + Bi + Ci + Di

Property
Models
(simple small molecules
& mixtures)
Electrolyte

Higher-order models (plus

gg more complex molecules & mixtures))
bigger
E
ymers

GC+ models (plus isomers & more complex

GC
Poly

molecules & systems)

M lti
Multi-scale
l models
d l (plus more complex systems and
structured chemicals)
Orrganic

A li ti range (qualitative)
Application ( lit ti )

Workshop on Product Design, NTUA, March 2011 37

Molecular Design (single molecule)

Workshop on Product Design, NTUA, March 2011 38

 Chemical product design framework
Essential,
E ti l
desirable
and EH&S
properties
Product &
process
evaluation
Build
molecules & Identify processes
mixtures; that can
verify their manufacture the
properties product sustainably

1. Define needs; 2. Design products; 3. Design

processes; 4. Evaluate process-product
39
Workshop on Product Design, NTUA, March 2011
 General Product Design Problem as MINLP
MINLP means Mixed Integer Non Linear Programming –
optimization problems formulated as MINLP contains
integer
g ((Y)) and continuous variables ((x, y) as optimization
p
variables, and, at least the objective function and/or one of
the constraints is non-linear.
Fobj = min {CTY + f(x, y, u, d, θ ) + Se + Si + Ss + Hc + Hp}
P = P(f,
( , x,, y, d,, u,, θ)) Process*/product
p model
0 = h1(x, y) Process/product constraints
0  g1(x,
( u, d) “Other” (selection)
constraints
0  g2(x, y)
Alternatives (molecules; unit
B x + CTY  D
operations; mixtures;
fl
flowsheets;
h t ….))
Workshop on Product Design, NTUA, March 2011 40
 2. Product Design: CAMD Framework
• Solutions of Start
CAMD problems
are iterative
iterative. No suitable
solutions (due to

• Problem Candidate
selection
performance,
economic or
safety concerns)
Problem
formulation (final verification/
comparison
p
formulation
(identify the
using rigorous
controls the simulation and
experimental Promising
goals of the
design operation)

success.
candidates have
procedures) been identified

• Essential
E ti l Result
analysis and
Method and
constraint
qualities vs. Finish
verification
(analyse the
selection
(specify the

((un)desirable
) suggested
compounds
using external
design criteria
based on the
problem
qualities. tools) formulation)

• Connectivity with CAMD

Solution
external
t l tools,
t l (identify
compound
data and having the
desired

methods. properties)

Workshop on Product Design, NTUA, March 2011 41

 CAMD General Problem Solution
3
3-stage Iterative
i Solution
S i Approach
A
1. Set Goals ((Pre-Design
g Stage)
g ) – Define Needs
• Essential properties
• Desirable properties
• Safety Environmental
Safety, Environmental, etc.
etc
2. Design/Selection (Design Stage) – Generate
Alternatives
• Search
S h through
th h database
d t b
• Iteratively build molecules/mixtures, comparing to goals
• Generate set of feasible molecules/mixtures
• Simultaneously build and evaluate molecules/mixtures
• Identify optimal molecule/mixture
• Identify y feasible set
3. Analyze, verify and select (Post-Design Stage) - Final
Selection (process/operation constraints)

Workshop on Product Design, NTUA, March 2011 42

 CAMD Problem Solution: Database Search

Problem: Find solvents that have

19.5 > Sol Par < 20.5
Solution:
S l ti U a search
Use h engine
i within
ithi a database
d t b tto
identify the set of feasible molecules

Workshop on Product Design, NTUA, March 2011 43

 CAMD Problem Solution: Enumeration
Multi-level generate & test according to a predefined sequence
Pre-design
g Design
g ((Start))

Interpretation to A set of building blocks: A collection of group

"I want acyclic input/constraints
CH3, CH2, CH, C, OH, vectors like:
alcohols, ketones, CH3CO, CH2CO, CHO, 3 CH3, 1 CH2, 1 CH,
aldeh des and ethers
aldehydes CH3O CH2O
CH3O, CH2O, CHCH-OO 1 CH2O
with solvent properties +
similar to Benzene" A set of numerical All group vectors
constraints satisfy constraints

Design (Higher levels) Start of Post-design

2.order Refined property CH2 CH2 CH3
CH2 CH2 CH3
group CH3 O CH estimation. Ability to CH3 O CH

estimate additional CH3

CH3
properties or use
CH3
CH3 alternative methods.
Group from CH2 CH CH3
CH2 CH CH3
other GCA CH3 O CH2
Rescreening against CH3 O CH2
method constraints.

Workshop on Product Design, NTUA, March 2011 44

Example of problem solution with ProCAMD

Workshop on Product Design, NTUA, March 2011 45

 Integrated Product-Process Design
Problem: A process stream of 50 mole% Acetone and 50
mole% Chloroform at 300K, is to be separated.
Separation
p techniques
q considered:
Adsorption (liquid, gas) N external
No t l medium
di known
k
Crystallization
Binary ratios of properties
Desublimation
identify the following
Distillation – simple
alternatives
Distillation – extractive
Distillation with decanter
Liquid-liquid extraction Separation techniques:
Flash/evaporation Distillation – simple
Membrane (g (gas,, liquid)
q ) Distillation – extractive
Microfiltration Distillation – azeotropic
Partial condensation Liquid extraction
h
Pressure swing

Note: Acetone-chloroform forms a high boiling azeotrope

that is ppressure sensitive

Workshop on Product Design, NTUA, March 2011 46

Pressure dependence

Workshop on Product Design, NTUA, March 2011 47

 Solvent design sub-problem

• CAMD problem: Solution:

• 340 < Tb < 420 1-Hexanal
• Selectivity
y > 3.5 y p y ether
Methyl-n-pentyl
• Solvent power> 2.0 (Benzene)
• No azeotropes
– 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

Workshop on Product Design, NTUA, March 2011 48

Phase behaviour

Workshop on Product Design, NTUA, March 2011 49

 Problem formulation & Solution

Objective function:
Maximize
Profit = Earnings
– Solvent cost
– Energy costs
Constraints:
Results:
Acetone purity > 0.99
S l
Solvent
t S l
Solvent
t Reflux
R fl Reflux
R fl Objective
Obj ti
Chloroform purity
flow>rate
0.98 Reb. 1 Reb. 2 function
1-hexanal 0.082 kmol/hr 0.45 0.65 2860.51 $/hr

Workshop on Product Design, NTUA, March 2011 50

 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:
gy Define CAMD p problem to ggenerate solvent
candidates; verify performance through solubility calculations;
check database to verify predictions

Workshop on Product Design, NTUA, March 2011 51

 Product Recovery: Crystallization
Chemical product: Ibuprofen
Consider
C id cooling
li as well ll as
drowning-out crystallization
Find solvents, anti-solvents & their mixture that satisfy the
following:
Potential recovery > 80%
Solubility parameter > 18 MPA1/2 (or > 30)
H d
Hydrogen b di solubility
bonding t > 9 MPA1/2 (or
l bilit parameter ( > 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
Workshop on Product Design, NTUA, March 2011 52
Product Recovery: Crystallization
Chemical product: Ibuprofen
Consider
C id cooling
li as well ll as
drowning-out crystallization

Workshop on Product Design, NTUA, March 2011 53

Product Recovery: Crystallization
Chemical product: Ibuprofen

Consider cooling as well as

drowning-out crystallization

Workshop on Product Design, NTUA, March 2011 54

 Case Study – Polymer Design: MINLP Applied to CAMD

Polymer design problem where polymer repeat units

with 2-4 different groups and 2-9 total number of
groups in the repeat unit structure are being sought

F bj =  [(Pi – Pi*)/Pi*]2
Fobj
s.t.
Tg  373 K
Density  1.5
1 5 g/cm3
Water absorption = 0.005 g H2O/g polymer)
-CH2- ; -CO- ; -COO- ; -O- ; -CONH- ; -CHOH-; -CHCL-

Workshop on Product Design, NTUA, March 2011 55

 Case Study – Polymer Design: MINLP Applied to CAMD

Fobj =  [(Pi – Pi*)/Pi*]2 select property models

st
s.t.
Tg = [ (Yknk)]/ [ (Mknk)]  (373  20) K

Density = [ (Mknk)]/ [ (Vknk)]  (1.5  0.1) g/cm3

W t absorption
Water b ti = [ (Hknk)]/ [ (Mknk)]

 (0.005 0.0005)) g H2O/gg p

polymer)
y )
-CH2- ; -CO- ; -COO- ; -O- ; -CONH- ; -CHOH-; -CHCL-
Note: objective function and constraints are non linear; nk,
the optimization variables are integer (0-9)

Workshop on Product Design, NTUA, March 2011 56

 Case Study – Polymer Design: MINLP Applied to CAMD

Fobj =  [(Pi – Pi*)/Pi*]2

st
s.t.
353 K < Tg = [ (Yknk)]/ [ (Mknk)] < 393 K

1.4 <  = [ (Mknk)]/ [ (Vknk)] < 1.5 g/cm3

0 0045 < W = [ (Hknk)]/ [ (Mknk)] < 0.0055)
0.0045 0 0055) g H2O/g polymer)
2  yj  3 ; yj : 0 or 1 for j=1,7
2  yknk  9 add structural constraints
-CH2-
CH2 ; -CO-
CO ; -COO-
COO ; -O-
O ; -CONH-
CONH ; -CHOH-;
CHOH ; -CHCL-
CHCL
Note: objective function and constraints are non linear; nk, the
optimization variables are integer (0-9)
(0 9)
Workshop on Product Design, NTUA, March 2011 57
 Case study – Polymer Design: Reformulate - I

Fobj =  [(Pi – Pi*)/Pi*]2

st
s.t.
353 K < Tg = [ (Yknk)]/ [ (Mknk)] < 393 K

1.4 <  = [ (Mknk)]/ [ (Vknk)] < 1.5 g/cm3

0 0045 < W = [ (Hknk)]/ [ (Mknk)] < 0.0055)
0.0045 0 0055) g H2O/g polymer)
50 <  (Mknk) < 100 add a new constraint
2  yj  3 ; yj : 0 or 1 for j=1,7
2  yknk  9
-CH2- ; -CO- ; -COO- ; -O- ; -CONH- ; -CHOH-; -CHCL-

Workshop on Product Design, NTUA, March 2011 58

 Case study – Polymer Design: Reformulate – II (MILP)

Min Fobj = M reformulate Fobj & constraints

st
s.t.
18.7 < TgM= [ (Yknk)] < 37.3 K g/mol

50/1.4 < M/ = [ (Vknk)] < 100/1.5 g/cm3

0 0045*50 < W M = [ (Hknk)] < 0.0055*100
0.0045*50 0 0055*100 g H2O/g polymer)
LB1  yj  UB1 ; yj : 0 or 1 for j=1,7
LB2  yknk  UB2
-CH2-
CH2 ; -CO-
CO ; -COO-
COO ; -O-
O ; -CONH-
CONH ; -CHOH-;
CHOH ; -CHCL-
CHCL
14 ; 28 ; 44 ; 16 ; 43 ; 30 ; 48.5

Workshop on Product Design, NTUA, March 2011 59

 MINLP Applied to CAMD: Exercise 2
G
Generate
t polymers
l that
th t match
t h the
th ffollowing
ll i target:
t t
Total number of
different main
groups:
5 for Problem 1
4 for Problem 2
4 for Problem 3
2  yjnj  5 ; yj : 0 or 1 for j=1,4
m=(v
( j -2)n
) j
0  yknk  m ; yk: 0 or 1 for k=5,8

Workshop on Product Design, NTUA, March 2011 60

 MINLP Applied to CAMD: Exercise 3
G
Generate
t molecules
l l thatth t match
t h the
th following
f ll i target:
t t
Min f=Hfus
180 < Tm < 225 K
400 < Tb < 440 K
-CH3 ; -CH2NO2; -CH3CO; -OH; -CH2=CH
-CH2-
yjnj = 4 ; yj : 0 or 1 for j=1,7
-CH-
CH
2  vjnj  3 ; yj : 0 or 1 for j=1,5
0  yknk  2 ; yk: 0 or 1 for k
k=6
6
0  ylnl  1 ; yl: 0 or 1 for l=7

Workshop on Product Design, NTUA, March 2011 61

 MINLP Applied to CAMD: Exercise-4
G
Generate
t molecules
l l thatth t match
t h the
th following
f ll i target:
t t
Min f= Cixi
LB1 < Tm = Tmi xi < UB2
LB2 < Vb = f(T,
f(T Tc, Pc, Zc, x) < UB2

Comp1, Comp2, Comp3, …………..CompN

yj= 2 ; yj : 0 or 1 for jj=1
1,N
N
0 < x1 < 1
0 < x2 < 1
x1 + x2 = 1
Workshop on Product Design, NTUA, March 2011 62
 Exercise Problems

Workshop on Product Design, NTUA, March 2011 63

 Tutorial Exercises

• Analyze the drug Ibuprofen (define the

needs
d ffor iimproving
i process efficiency
ffi i in
i
extracting the product from solution in
the reactor) – use ProPred
• Use ProCamd to match the list of solvents
and anti-solvents for Ibuprofen
• Solve
S l theh organici synthesis
h i problems
bl with
ih
ProCamd

See slides 53-55

Workshop on Product Design, NTUA, March 2011 64
 Exercises
• Analyze the drug Ibuprofen (define the
needs for improving
p gp
process efficiency
y in
extracting the product from solution in
the reactor) – use ProPred
– Search compound in database
• start ICAS
• click on M, select basic search, search with CAS-
number
b (015687
(015687-27-1),
27 1) copy SMILES
– Start ProPred
• import SMILES, analyze properties

Workshop on Product Design, NTUA, March 2011 65

 Exercises

• Use ProCamd to match the list of solvents

and anti-solvents for Ibuprofen
– Formulate problems (solvent & anti
anti-solvent)
solvent)
see slides 53-55)
• Start ProCamd
– Specify problem (ProCamd manual)
– Start execution
– Analyze results

Workshop on Product Design, NTUA, March 2011 66

 Other chemical product design problems – 1a

Problem Statement-1: From the derivatives of Barbituric

acid, identify the candidate that is required in the smallest
amount (C) to produce a 1:1 complex with protein (binding
to bovine serum albumin)

Barbituric Acid
(000077-02-1)

Workshop on Product Design, NTUA, March 2011 67

 Other chemical product design problems – 1b
Problem Statement
Statement-1:1: From the derivatives of Barbituric
acid, identify the candidate that is required in the smallest
amount (C) to produce a 1:1 complex with protein (binding
to bovine serum albumin))

Barbituric Acid (000077-02-1)

Calculate C as a function of octanol-water partition coefficient

of the candidate compounds: Log10(1/C) = 0.58 log10P + 0.239

Workshop on Product Design, NTUA, March 2011 68

 Other chemical product design problems – 1c
Problem Statement-1: From the derivatives of Barbituric acid, identify
the candidate that is required in the smallest amount (C) to produce a
1:1 complex
p with protein
p (binding
( g to bovine serum albumin))

Barbituric Acid (000077-02-1)

(000077 02 1)

Calculate C as a function of octanol-water partition coefficient of the

candidate compounds: Log10(1/C) = 0.58
0 58 log10P + 0.239
0 239
Question: How is the backbone (barbituric acid) identified and how is
the relation ((drugg activity)
y) between C vs log
g10P ffound?

Workshop on Product Design, NTUA, March 2011 69

 Other chemical product design problems – 1d
Problem Statement-1: From the derivatives of Barbituric acid, identify
the candidate that is required in the smallest amount (C) to produce a
1:1 complex
p with protein
p (binding
( g to bovine serum albumin))

Barbituric Acid (000077-02-1)

(000077 02 1)

Calculate C as a function of octanol-water partition coefficient of the

candidate compounds: Log10(1/C) = 0.58 log10P + 0.239
Solution Steps: Generate candidates; calculate LogP; calculate C; order
solutions w.r.t.
w r t C to identify the best candidate; check for solubility in water

Workshop on Product Design, NTUA, March 2011 70

 Other chemical product design problems – 1e
Problem Statement-1: From the derivatives of Barbituric acid, identify
the candidate that is required in the smallest amount (C) to produce a
1:1 complex
p with protein
p (binding
( g to bovine serum albumin))

Solution Steps
•Generate candidates (check database)
•Use ProPred to calc LogP and LogWs
•Calculate C

Barbituric Acid (000077-02-1)

(000077 02 1) •Order solutions with respect
p to C

Calculate C as a function of octanol-water partition coefficient of the

candidate compounds: Log10(1/C) = 0.58 log10P + 0.239
Candidates (CAS Numbers) : 061346-87-0; 000076-94-8; 091430-64-7;
001953-33-9; 007391-69-7; 090197-63-0; 017013-41-1; 027653-63-0

Workshop on Product Design, NTUA, March 2011 71

 Other chemical product design problems – 2a
Problem Statement-2 (Design of backbones & termination of backbones): In this
problem, we will start with ProPred, take a known molecule (for example,
Corticosterone), use the features in ProPred to create free attachments in the
molecule (that is, create a backbone). The Backbone is then transferred to
ProCamd, where terminated structures are generated (see page 53 of tutorial document)
Step 1: Start ProPred from ICAS
Step 2: Click on (database) , click on “Find CAS”, type the CAS Number for
Corticosterone (00005-22-6), select the compound by clicking on OK
Step 3: ProPred draws the molecule and predicts the properties
Step 4: Remove the OH group connection from the molecular structure at the
two locations
Step 5: Launch ProCamd from ProPred from the tools menu in ProPred.
ProPred
Step 6: Fill-out the necessary problem definition pages in ProCamd (general
problem control, non-temperature dependent properties)
Step 7: Terminate the backbone by clicking on “GO”.
Step 8: Save the backbone-termination problem as “save ProPred backbone
problem” under the file menu. To use this file later, the saved backbone file
must be loaded from the file menu.
Workshop on Product Design, NTUA, March 2011 72
 Other chemical product design problems: 2b
Problem Statement
Statement-2
2 (Construct backbones & terminate with
ProCamd): Use Corticosterone as an example

Step 2
St 2: Cli
Click
k on (d
(database)
t b ) , click
li k on “Find
“Fi d CAS”,
CAS” ttype
the CAS Number for Corticosterone (00005-22-6), select
the compound by clicking on OK

Workshop on Product Design, NTUA, March 2011 73

 Other chemical product design problems: 2c
Problem
P bl Statement-2
St t t2
(Construct backbones &
terminate with ProCamd):
Use Corticosterone as an
example
Step 3: ProPred draws
the molecule and
predicts the properties

Workshop on Product Design, NTUA, March 2011 74

 Other chemical product design problems: 2d
Problem
P bl Statement-2
St t t2
(Construct backbones &
terminate with ProCamd):
Use Corticosterone as an
example

Step
p 4: Remove the OH
group connection from
the molecular structure at
the two locations

Backbone with two-free attachments.

Note that as ProCamd generates
g
molecular structures only with the
Constantinou & Gani groups, it must be
possible for the Constantinou & Gani
method to represent the backbone.
Otherwise, ProPred will not launch
ProCamd

Workshop on Product Design, NTUA, March 2011 75

 Other chemical product design problems: 2e
Problem
P bl Statement-2
St t t2
(Construct backbones &
terminate with ProCamd):
Use Corticosterone as an
example

Step 6: Fill-out the

necessary problem
definition pages in
ProCamd (general
problem
bl control,
t l non-
temperature dependent
properties)

Workshop on Product Design, NTUA, March 2011 76

 Other chemical product design problems: 2f
Problem
P bl Statement-2
St t t2
(Construct backbones &
terminate with ProCamd):
Use Corticosterone as an
example

Step 7: Terminate the

backbone by clicking on
“GO”.

Note that for backbone

termination step, the options for
P P d properties
ProPred ti and d database
d t b
search cannot be used.

Workshop on Product Design, NTUA, March 2011 77

 Other chemical product design problems: 3a
Problem Statement
Statement-33 (Generate & terminate backbones):In this problem,
problem we
will first generate a backbone with ProCamd using only the C & H atoms and
with 1 free-attachment in the backbone. We will then go to ProPred to draw the
molecular
o ecu a st
structure
uctu e a
and
d work
o o on tthe
e st
structure
uctu e without
t out terminating
te at g the
t e
structure. We will then launch ProCamd from ProPred to find the final
terminated structure through ProCamd (see pages 53-60 in tutorial document)
Step 1: Start ProCamd and specify the following backbone generation
problem.
Step 2: Run ProCamd to generate the backbone alternatives. Note that for the
backbone generation, “isomer” generation is not allowed. For the problem
formulated in step 1, the following result is obtained.
Step 3: Click on ProPred to transfer the backbone structure.
structure Propred draws the
structure and calculates all properties, as shown below.
Step 4: Launch ProCamd from ProPred from the “tools” menu
A new ProCamd application is opened. ProPred sends back the same
backbone structure that ProCamd generated.
Step 5: Complete the backbone termination problem with ProCamd.
ProCamd

Workshop on Product Design, NTUA, March 2011 78

 Other chemical product design problems: 3b
Problem Statement-
3 (Generate
backbone with
ProCamd &
terminate manually
with ProPred)

Step 1: Start
P C d and
ProCamd d
specify the
following
backbone
generation
p
problem.

Note: at this stage specification of any other property is not necessary

Workshop on Product Design, NTUA, March 2011 79
 Other chemical product design problems: 3c
Problem Statement-3
(Generate backbone
with ProCamd &
terminate manually
with ProPred)

Step 2: Run ProCamd to

generate the backbone
alternatives.
l i Note
N that
h for
f
the backbone generation,
“isomer” generation is not
allowed. For the problem
formulated in step 1, the
followingg result is obtained.

Workshop on Product Design, NTUA, March 2011 80

 Other chemical product design problems: 3d

Problem Statement-3
(Generate backbone
with ProCamd &
terminate manually
with ProPred)

Step 3: Click on
ProPred to
transfer the
backbone
structure. ProPred
d
draws the
th
structure and
calculates all
properties, as
shown below.

Workshop on Product Design, NTUA, March 2011 81

 Other chemical product design problems: 3e
Problem Statement-3
(Generate backbone
with ProCamd &
t
terminate
i t manuallyll
with ProPred)

Step 4: Launch
ProCamd from ProPred
from the “tools” menu
A new ProCamd
application is opened.
ProPred sends back
the same backbone
structure that
ProCamd generated.
Step 5: Complete the
backbone termination
problem with
ProCamd.

Workshop on Product Design, NTUA, March 2011 82

 Other chemical product design problems: 3f
Problem Statement-3 ProCamd generates 74 terminated
(Generate backbone
with ProCamd & structures out of which
terminate manually compound d 1 is
i Ibuprofen
Ib f
with ProPred)

Step 4: Launch
ProCamd from ProPred
from the “tools” menu
A new ProCamd
application is opened.
ProPred sends back
the same backbone
structure that
ProCamd generated.
Step 5: Complete the
backbone termination
problem with
ProCamd.

Workshop on Product Design, NTUA, March 2011 83

 Other chemical product design problems: 4a
Problem Statement-4 (Design large molecules):
Design a large molecule having the following
p p
properties,
Mw > 300
See page 61 of tutorial
Tb > 400 K document
Tm > 300 K

Solve the problem with ProCamd and then switch to

ProPred and further investigate the properties of the
l
large molecule,
l l including
i l di further
f h increase
i off the
h size
i
of the molecule. Only the “general problem control”
and the “non-temperature
non-temperature depd props”
props need to be
specified.

Workshop on Product Design, NTUA, March 2011 84

 Other chemical product design problems: 4b
Problem Statement-4 Design a large
molecule having the following
p p
properties,
Mw > 300; Tb > 400 K; Tm > 300 K

Solve the problem with

ProCamd and then switch
to ProPred.

Repeat the problem for acyclic

compoundsd andd cyclic
li
compounds

Workshop on Product Design, NTUA, March 2011 85

 Exercises: summary

• Solve example problem 1 (find best AI)

• Solve example problem 2 (backbone
termination)
• Solve example problem 3 (backbone
generation & termination)
• Solve example problem 4 (generate large
molecules, pass to ProPred and then
analyze and further develop )

Workshop on Product Design, NTUA, March 2011 86

 Summary
• For computer aided product-process design,
models are necessaryy
– If appropriate models are available, almost all
problems can be solved
• Solution of different product-process design
problems need a good understanding of the
problems so that the available tools can be
applied correctly and efficiently
• Problems related to low
low-value
value products are easier
to solve than the high-value products
– The limiting factors for these problems are availability
of data and appropriate models

Workshop on Product Design, NTUA, March 2011 87