Sigma profile generation with

conceptual segment approach

Md Rashedul Islam
Outline
Background
Objective
Solvation thermodynamics
Conceptual segment idea
Sigma profile generation model formulation
Results and Discussion
Conclusion


Background
A priori prediction of fluid phase equilibria and liquid phase non-
idealities are key factors in process and product development

Thermodynamic behavior is calculated/predicted based on group-
contribution methods, activity-coefficient models, and solvation-
thermodynamics

Solvation-thermodynamic approach predicts thermo-physical
properties based on molecular structure only


Motivation
Among the solvation thermodynamic based models, COSMO-RS
and COSMO-SAC are the are well recognized

A key input to these models is so called Sigma Profile, i.e. a
histogram of charge density distribution over molecular surface

Typically -profile is generated using quantum mechanical
calculation

Interested researchers are intimated by the complexity of quantum
mechanical calculation to use COSMO-based model
Objective
We introduce conceptual segment based concept of NRTL-SAC
activity coefficient model

We select four reference solvents to represents hydrophobic,
solvation, polar, and hydrophilic conceptual segments

We generate -profile of any molecules from the linear
combination of -profile of four reference solvents

We identify the conceptual segment numbers from fitting available
solubility date involving the molecules and four reference solvents
or their equivalents

We predict the solubility of three drug molecules to validate our
methodology

Thermodynamic Background
Solubility Thermodynamics





Activity coefficient models:
UNIFAC
NRTL-SAC
COSMO-SAC

Theoretical structure of activity coefficient

= +

: mole fraction of solute at saturation

: activity coefficient of solute

: heat of fusion of solute

T

: melting temperature of solute

: solubility product constant

NRTL-SAC model
A derivative of NRTL model
A practical thermodynamic framework for solubility modeling
Surface interaction characteristics of a molecules are exploited
Qualitative parameters are identified from representative solvents:
hydrophobic, polar, and hydrophilic

Due to multiple crystalline structure, multiple melting point or
latent heat of fusion may exist
Ksp is estimated through regression using experimental solubility
NRTL-SAC predicts solubility better than COSMO-SAC does
Thermodynamic Background
Solubility Thermodynamics





Activity coefficient models:
UNIFAC
NRTL-SAC
COSMO-SAC

Theoretical structure of activity coefficient

= +

: mole fraction of solute at saturation

: activity coefficient of solute

: heat of fusion of solute

T

: melting temperature of solute

: solubility product constant

Solvation Thermodynamic Model
Predict inter-molecular interactions based on molecular
structure
Characterize liquid phase non-ideality
Computational quantum mechanics is used to predict thermo-
physical properties
Models: COSMO-RS
1
and COSMO-SAC
2

COSMO-based models require sigma profile as input

Sigma profile is a molecular-specific distribution of surface-
charge density



1. Klamt et al
2. Lin and Sandler
COSMO-SAC Model
COSMO-SAC model predict thermo-physical properties based
on solvation free energy
Solvation free energy represents Gibbs free energy required
to bring a moving molecule from a fixed position in ideal state
to a fixed position in solution
Solvation free energy is related
to activity coefficient
Lin and Sandler, 2002
Sigma Profile
Sigma profile is a measure of molecules dipole and higher
moment interaction with surrounding medium
Probability distribution of surface-charge density of a
molecule or a mixture,

()
-0.025 -0.02 -0.015 -0.01 -0.005 0 0.005 0.01 0.015 0.02 0.025
0
5
10
15
20
25
30
35
, e/Ang
2
P
(

)
*
A
(

)
,

A
n
g
2


Hexane
DMSO
Nitromethane
Water
Sigma profile of a
mixture is a weighted
average of the pure
components.
Merits and Demerits of COSMO-SAC Model
Useful for priori estimates of thermo-physical properties of
new and unmeasured species
Predicts phase equilibria for new mixture
Merits
Sigma profile is highly subjected
to structural conformation
Over and under prediction of
solubility likely observed
Demerits
Proposed Idea
Conceptual segment, i.e. X,Y
+
, Y
-
, and Z, idea from NRTL-SAC
is introduced into COSMO-SAC
Sigma profile is generated from the linear combination of
sigma profile of reference molecules
Like NRTL-SAC, reference molecules are hydrophobic, polar,
and hydrophilic
Cavity volume is calculated from the cavity volume and
conceptual segment parameters
X,Y
+
, Y
-
,Z are estimated from experimental solubility
Ksp value is also regressed if necessary


Parameter Regression Algorithm
Non-linear regression is due to non-linearity of COSMO-SAC
Constrained optimization is employed for non-negativity of
sigma profile


Results and Discussion
Proposed algorithm is implemented to predict the solubility of
three drug molecules: Caffeine, Aspirin, and Acetaminophen

For each drug, solubility is reported based on the sigma
profile from Virginia Tech(VT) database

Solubility of each drug is calculated from new sigma profile
and reported alongside VT results to demonstrate
improvement

For Acetaminophen, solubility in different binary solvent is
also predicted

Results and Discussion
Caffeine
0
3
6
9
12
15
18
21
24
27
-0.03-0.025-0.02-0.015-0.01-0.005 0 0.005 0.01 0.015 0.02 0.025 0.03
S
i
g
m
a

P
r
o
f
i
l
e
,

P
(

)
*
A
i

(

2
)

Screening Charge Density, (e/
2
)
Sigma Profile of Caffeine
COSMOSAC VT
COSMOSAC-XYZ
Solvent Experimental solubility
N-HEXANE 3.94E-06
2-ETHOXYETHANOL 0.006779
1-OCTANOL 0.002455
1,4-DIOXANE 0.008204
N,N-DIMETHYLFORMAMIDE 0.012558
WATER 0.002247
ETHANOL 0.0017
ETHYL-ACETATE 0.00409
Results and Discussion
Caffeine
Regression Results
Hf & Tm Ksp
X 0 0
Y+ 0.4296 0.4675
Y- 1.2710 1.2044
Z 0.2553 0.1619
Cavity volm 137.88 134.56
1.E-06
1.E-05
1.E-04
1.E-03
1.E-02
1.E-01
1.E-06 1.E-05 1.E-04 1.E-03 1.E-02 1.E-01
M
o
d
e
l

s
o
l
u
b
i
l
i
t
y
,

x
m
o
d
e
l

Experimental solubility, x
exp
Caffeine: COSMOSAC Regression
Hf & Tm
Ksp
VT
Hexane
Water
Results and Discussion
Aspirin
Solvent Mole Frac.
METHANOL 0.080530
ACETONE 0.116300
ETHANOL 0.060070
1,4-DIOXANE 0.102900
ACETIC-ACID 0.043470
METHYL-ETHYL-KETONE 0.051740
ISOPROPYL-ALCOHOL 0.059240
3-METHYL-1-BUTANOL 0.051550
CHLOROFORM 0.040570
DIETHYL-ETHER 0.021190
1-OCTANOL 0.021860
1,2-DICHLOROETHANE 0.016700
1,1,1-TRICHLOROETHANE 0.003706
CYCLOHEXANE 2.335E-05
0
2
4
6
8
10
12
14
16
18
-0.03 -0.025 -0.02 -0.015 -0.01 -0.005 0 0.005 0.01 0.015 0.02 0.025 0.03
S
i
g
m
a

P
r
o
f
i
l
e
,

P
(

)
*
A
i

(

2
)

Screening Charge Density, (e/
2
)
Sigma Profile of Aspirin
COSMOSAC VT
COSMOSAC-XYZ
XYZKsp
Results and Discussion
Aspirin
1.E-05
1.E-04
1.E-03
1.E-02
1.E-01
1.E+00
1.E-05 1.E-04 1.E-03 1.E-02 1.E-01 1.E+00
M
o
d
e
l

s
o
l
u
b
i
l
i
t
y
,

X
m
o
d
e
l

Experimental solubility, X
exp
Aspirin: COSMOSAC Regression
COSMOSAC VT
COSMOSACXYZ
Hf & Tm
Regression Results
Hf & Tm Ksp
X 0.0357 0.0802
Y+ 0.0837 0.0845
Y- 0.6555 0.6281
Z 0.5716 0.5869
Cavity volm 74.04 79.10
Results and Discussion
Acetaminophen (Paracetamol)
0
2
4
6
8
10
12
14
16
18
20
22
-0.03 -0.025 -0.02 -0.015 -0.01 -0.005 0 0.005 0.01 0.015 0.02 0.025 0.03
S
i
g
m
a

P
r
o
f
i
l
e
,

P
(

)
*
A
i

(

2
)

Screening Charge Density, (e/
2
)
Sigma Profile of Acetaminophen
COSMOSAC VT
COSMOSAC-XYZ
XYZKsp
SOLVENT Solubility Mole fraction
WATER 17.39 0.002068
METHANOL 371.61 0.073012
ETHANOL 232.75 0.066232
ETHYLENE-GLYCOL 144.3 0.055935
1-PROPANOL 132.77 0.050135
ISOPROPYL-ALCOHOL 135.01 0.050941
N-BUTANOL 93.64 0.043897
1-PENTANOL 67.82 0.038043
1-HEXANOL 49.71 0.038014
1-HEPTANOL 37.43 0.027967
1-OCTANOL 27.47 0.023118
ACETONE 111.65 0.041132
METHYL-ETHYL-KETONE 69.99 0.032308
METHYL-ISOBUTYL-KETONE 17.81 0.011663
TETRAHYDROFURAN 155.37 0.069000
1,4-DIOXANE 17.08 0.009857
ETHYL-ACETATE 10.73 0.006215
ACETONITRILE 32.83 0.008836
DIETHYL-AMINE 1316.9 0.389184
N,N-DIMETHYLFORMAMIDE 1012.02 0.328548
DIMETHYL-SULFOXIDE 1132.56 0.369225
ACETIC-ACID 82.72 0.031814
DICHLOROMETHANE 0.32 0.000180
CHLOROFORM 1.54 0.001215
CARBON-TETRACHLORIDE 0.89 0.000905
TOLUENE 0.34 0.000207
Results and Discussion
Acetaminophen (Paracetamol)
Regression Results
4 para. 5 para.
X 0.2980 0.6291
Y+ 0.0379 0
Y- 0 0
Z 1.3652 1.3142
Ksp -3.5364
Cavity volm 82.43 125.75
1.E-07
1.E-06
1.E-05
1.E-04
1.E-03
1.E-02
1.E-01
1.E+00
1.E-07 1.E-06 1.E-05 1.E-04 1.E-03 1.E-02 1.E-01 1.E+00
M
o
d
e
l

s
o
l
u
b
i
l
i
t
y
,

X
m
o
d
e
l

Experimental solubility, X
exp
Acetaminophen: COSMOSAC Regression
COSMOSAC VT COSMOSACXYZ XYZKsp
Results and Discussion
Hydrophilic-hydrophilic pair
Methanol-water binary Ethanol-water binary
Results and Discussion
polar-hydrophilic pair
Acetone-water binary 1,4-dioxane-water binary
Results and Discussion
Polar-hydrophobic pair
Acetone-toluene binary
Results and Discussion
Hydrophilic-hydrophobic pair
Methanol-ethyl acetate binary Ethanol-ethyl acetate binary
Conclusion
The proposed methodology offers a very simile and practical
approach to generate -profile
This method generate -profile of any molecule in terms of
conceptual segment numbers
Conceptual segment numbers are in turn identified by fitting
against experimental solubility data in solvents of various nature
The methodology requires no knowledge of molecular structure nor
molecular conformation and no use of DFT calculations or quantum
chemistry packages
The generated -profile perform well in COSMO-based predictions
of thermophysical properties.

Reference