Using COSMOtherm.A Pharmaceutical Industry Perspective

Simone Tomasi5th COSMO-RS Symposium

Pharmaceutical Technology & Development

Macclesfield site (UK)

Pharmaceutical Development

• How to formulate the product?

• How to deliver the product to the patient?

• How to manufacture the product?

• How to package the product?

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• Identify preferred chemical route

• Develop ways of achieving route

• Provide process understanding

• Define ranges within which process is robust

Milling Mixing Granulation

Compaction

Packaging

Device

M&DFilling

Tablet

DPI

There is more to it than

tablets and dry powder

inhalers, but ...

Starting with the target pharmaceutical

profile, Product Development is about

Chemical Development is about designing and

developing processes to enable supply of API

that performs in the product and in the patient

A

B

C

API

Route Design

Process Design

Process

characterisation

and optimisation

S AFETY

E NVIRONMENTAL

L EGAL

E CONOMICS

C ONTROL

T HROUGHPUT

Route

Starting material

Intermediates

Co

ntr

ol str

ate

gy

Other applications•Solid state predictions

•Spectra simulations in the NMR, IR and UV-vis

•....

▪ Process Understanding

• Mechanistic studies

• Answer the question “what happens and why?”

Computational Chemistry in Chemical Development

▪ Route design

• Predictive catalysis/ligand screening

• Fast regioselectivity predictions

• pKa predictions (aqueous and organic)

▪ Process design

• Solvent selection (reaction,

work-up & isolation)

• Solvent swaps

• Extraction design

• Impurity rejection

• Crystallisations

Quantum Mechanics calculations for...

E2

E1

G

Reaction coordinate

R+ E

R

EH

+

EH

R

+

R

E

ER

Aromatic substitutions

-2

0

2

4

6

8

10

12

14

-0.03 -0.02 -0.01 0 0.01 0.02 0.03

FU (a)

Sigma-profile (QM)

Reaction coordinateReactants

DABCO-catalysed

TS1

MI-

DABCOH+-catalysed

TS2 (F- elimination)

Non-catalysed

TS2 (F- elimination)

Products

VLE simulations

Solubility profiles

or NRTL/UNIFAC parameters

Partition equilibria

Aqueous

Organic

BCME BCMS

BCME BCMS

SO42-

HCO3-

Na+ K+

Cl-

Rig-D

Rig-D

logP=3.9 logP=2.4 logP=3.6

Other applications•Solid state predictions

•Spectra simulations in the NMR, IR and UV-vis

•....

▪ Process Understanding

• Mechanistic studies

• Answer the question “what happens and why?”

Computational Chemistry in Chemical Development

▪ Route design

• Predictive catalysis/ligand screening

• Fast regioselectivity predictions

• pKa predictions (aqueous and organic)

▪ Process design

• Solvent selection (reaction,

work-up & isolation)

• Solvent swaps

• Extraction design

• Impurity rejection

• Crystallisations

Quantum Mechanics calculations for...

E2

E1

G

Reaction coordinate

R+ E

R

EH

+

EH

R

+

R

E

ER

Aromatic substitutions

-2

0

2

4

6

8

10

12

14

-0.03 -0.02 -0.01 0 0.01 0.02 0.03

FU (a)

Sigma-profile (QM)

Reaction coordinateReactants

DABCO-catalysed

TS1

MI-

DABCOH+-catalysed

TS2 (F- elimination)

Non-catalysed

TS2 (F- elimination)

Products

VLE simulations

Solubility profiles

or NRTL/UNIFAC parameters

Partition equilibria

Aqueous

Organic

BCME BCMS

BCME BCMS

SO42-

HCO3-

Na+ K+

Cl-

Rig-D

Rig-D

logP=3.9 logP=2.4 logP=3.6

6

Solvent selectionTasks of solvents in a process:

• Dissolve reagents in a reaction

• Remove impurities and co-products

during work-up

• Isolate pure solid product with form

and particle control

• Clean reactor for re-use

Useful data:

• Solubility (main product; other solutes when possible)

• Water/organic partition coefficients of all product and impurities

• Acid dissociation constants

• LLE and VLE behaviour of candidate solvents

• In-house database of 272 solvents to consider

Reaction solvent(s)

Solvents for work-up (extractions)

Solvents for isolation (crystallisations)

Plant cleaning solvents

Reaction solvent selection

compatible

functional

groups

Melting

point

Boiling

point

ICH class

other

properties

Constraints

Subset of

compatible solventsReaction

Type of

chemistry

Nature of

reagents

Required

T

Input information

Process

impurities

The Solvent Selection Tool

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• Solvent Selection is complex process.

– Selecting the ‘right’ solvent early on can have huge benefits.

• The tool allows for the consideration of multiple criteria (Graphical Approach).

• Focus on the needs of the process solvent shortlist.

Shortlist

Process

needs

Solvent

toolSolvent

tool

Solvent list

Experimentation

And

Simulation

Solute

specifics

Org. Process Res. Dev., 2016, 20, 760–773 DOI: 10.1021/acs.oprd.6b00015 David Hose

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Solvent selection for work-up & isolation

same

diffe

rent

no

yes

compatible

functional

groups

cost

availability

ICH class

other

properties

Constraints

yes

noSubset of

compatible solventsSolvents short list

Isolation

solventsExtraction

solvents

Partition

coefficients,

pKa’sSolubilities VLE

Check

water

miscibility

Check

viable

process

volume

Make sure

solvent swap

is possible

Impurities

present?

Isolate

solid

product?

Solvent in

next

stage?

same

diffe

rent

no

yes

compatible

functional

groups

cost

availability

ICH class

other

properties

Constraints

yes

noSubset of

compatible solventsSolvents short list

Isolation

solventsExtraction

solvents

Partition

coefficients,

pKa’sSolubilities VLE

Check

water

miscibility

Check

viable

process

volume

Make sure

solvent swap

is possible

Impurities

present?

Isolate

solid

product?

Solvent in

next

stage?

10

Solvent selection for work-up & isolation

Partition

coefficients,

pKa’sSolubilities

COSMOtherm

CH3CN

Et3N

pKa = 3.9pKa = 4.9

11

Process design example: extraction solvent selection

Aims

1. Remove Et3NH+Cl-

2. Remove 2-regioisomer

3. Carry through to next

stage as solution

Constraints

1. Organic solvent immiscible with

CH3CN or water/CH3CN

2. Enabling an efficient extraction

3. Higher boiling than CH3CN

Mark Graham

12

LogP of main product vs LogP

LogP

Ma

in p

rod

uct L

ogP

All solvents LogP values

COSMOtherm 2016

BP-TZVPD-FINE

Mark Graham

13

Choosing solvent for extraction into acidic aqueous phase

LogP

Ma

in p

rod

uct L

ogP

LogP values without

• ICH Class 1 solvents

• Some solvent classes

• Tboil < 200 °C

MTBE

Toluene

Alkanes

CPME

TAME

Mark Graham

14

Two work-up strategies

End of reaction

CH3CN mixture

Add water

Extract into

organic solvent

Extract into

acidic aqueous

Neutralise &

extract into

organic solvent

Swap to

organic solvent

Extract into

acidic aqueous

Wash with

water

Neutralise &

extract into

organic solvent

Organic solution for next stage

Reject Et3NH+Cl-

to aqueous phase

Reaction products

stay in organic phase

Product in aqueous phase

Regioisomer in organic phase

TolueneHeptane

Chosen Heptane.

Reaction solvent changed

from CH3CN to DMSO.

Final extraction with MTBE.

Distil off CH3CNRequired for Toluene only

TolueneHeptane

End of reaction

CH3CN mixture

Mark Graham

• What is the best way to predict solubility with COSMOtherm?

• How accurate are the predictions?

15

Solubility predictions

Approximation:

Justified only near to Tm

→error estimating Gfus!

How does COSMOtherm predict solubility?

16

Solute(s)

Gfus

SGmix

Solute(sol)

Solute(l) log10ሺ𝑥S) =mxx − mS

x − ∆Gfusx

RTln10

RTln10 ∙ log10ሺ𝑥S) = mxx − mS

x − ∆Gfusx

= m𝐒ሺ𝐬𝐨𝐥𝐢𝐝)𝒙 − m𝑺

𝒙 = 𝑹𝑻𝒍𝒏ሺ𝒙𝑺)

• Gfus from DSC data (standard approach)

• Gfus from reference solubility

∆𝐶𝑝𝑓𝑢𝑠~0

∆Gfusx = mx

x − mSx − RTlnሺ𝑥S)

∆𝑆𝑓𝑢𝑠= ∆𝐻𝑓𝑢𝑠/𝑇𝑚

Gfus known at the T of the reference solubility

No knowledge of T dependence

∆𝐺𝑓𝑢𝑠= ∆𝐻𝑓𝑢𝑠 − 𝑇∆𝑆𝑓𝑢𝑠 − ∆𝐶𝑝𝑓𝑢𝑠 𝑇𝑚 − 𝑇 + 𝑇∆𝐶𝑝𝑓𝑢𝑠𝑙𝑛𝑇𝑚𝑇

Effect on predictions of experimental variation in DSC data

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• COSMOtherm16, BP-TZVPD-FINE, absolute solubility (iterative), Gfus from DSC

• Not interested in a comparison with experiment!

• Variation of predictions exclusively due to different input Hfus and Tm

• Single AZ compound; 9 measured Hfus/Tm

values

• 9 predicted values for each solvent; 259

solvents

• For each solvent plot distribution of

Ln(w_solub)

• Std Dev values from each solvent similar but

not identical

• Distribution plot of all Std Dev values gives an

average Std Dev

• Average Std Dev = 0.66 Ln units

• Due only to variation in DSC data

Variation of experimental DSC data caused a

factor of ~2 variation in predicted solubility

# Hfus

(kJ/mol)

Tm

(°C)

1 45 207

2 48 208

3 34 207

4 40 209

5 38 206

6 42 205

7 36 206

8 39 207

9 39 205

MeOH

Not all reference solvents are made equal!

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• Previous internal AZ work: ACETONITRILE on average appears to provide

the best experimental reference solubility data for COSMOtherm solubility.

• The expected model error is a factor of ~3 (assuming no experimental error).

BP/TZVPD-FINE COSMOtherm16Zachary Lockhart

ACN

FINE_16 Log(Predicted) vs Log(EXP) by reference

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ACN RMSE = 0.53Acetone RMSE = 0.76

DSC RMSE = 0.78 QSPR RMSE = 1.41

RMSE = 0.44

(H2O and Heptane

outliers removed)

MeTHF RMSE = 0.60

H2O RMSE = 1.77

RMSE = 0.65

(H2O and Heptane

outliers removed)

COSMOtherm16 vs COSMOtherm17

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For other reference solvents the mean also varied

THF iPrOH

Reference solvent: ACN

The 2016 parameterisation performed better!

AZ Solubility prediction decision tree

Best possible approach First choice alternative

approach

Second choice

alternative approach

Choose as a last

resort

1.

Multiple solubilities

from internal thermodynamic

solubility screening

available?

2.

Are other

thermodynamic solubility

data in multiple solvents

available?

3.

Is the solubility in

ACN* known?

4.

Can it be

measured?

7.

Can a DSC from a

sufficiently pure sample

(>98% assay) be

obtained?

6.

Is the DSC data usable? (no solid state transformations /

desolvation / decomposition obscuring

the main melt)

5.

Is DSC data from a

sufficiently pure sample

(>98% assay)

available?

Absolute solubility

calculation with

Gfus estimate from

best reference

solvent

Absolute solubility

calculation with

Gfus estimate from

DSC

Absolute solubility

calculation with

Gfus estimate from

ACN reference

solvent

Absolute solubility

calculation at 25 °C

with Gfus estimate

from QSPR

yes

no

yes

no

no

no

yes

yes

yes

no

no

noSTART

* other solvents may

also be suitable.

• What is the best way to predict solubility with COSMOtherm?

• How accurate are the predictions?

22

Solubility predictions

• All following conclusions need to be confirmed with a larger data set.

• BP-TZVPD-FINE (2016 parameters) was the “flavour” of COSMO-RS that performed best.

• Variation of DSC experimental values has a strong influence on solubility predictions.

• Solubility predictions with COSMO-RS often work better using reference solubility data.

− COSMO-RS TZVPD-FINE predictions (2016 parameterization), acetonitrile reference

solubility data: RMSE = 0.53 Log units (0.44 excluding outliers).

− Using DSC as input: RMSE = 0.78 Log units (0.65 excluding outliers).

• Not yet clear if a single default solvent can work well enough as a reference for all solutes.

Development challenges

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• Effects of ions in solution

– Ion supermolecules with optimal number of waters

– Implementation of COSMO-RS-PDHS into COSMOtherm

• Oiling out

– Fast and reliable way to compute and plot SLLE for ternary systems

• Interaction Energy Indices

– Great concept, necessary for treating well dimerization problems

– How could its use be made easier?

• Solubility of salts of pharmaceutical compounds

– Currently inaccurate even for salts of simple organics

Models for ions in solution

Ion-water supermolecule approach

• How many waters?

• “Easy” for metal cations and

monoatomic anions

Searchlight for water # optimization:

balance s-profiles not exceeding much

the s range span by water vs complexity

Larger anions (CO32-, SO4

2-, PO43-)

are more difficult

• More highly charged

• Multiple conformations of the

ion-water(s) supermolecule

Chem Eng Res Des, 2014, 92, 2873-2883

Can COSMOtherm predict salting out?

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Effect of electrolytes on:

• Number of liquid phases

• Amount of water in organic phase

• Partition of solute

Process relevant conditions

Aqueous

Organic

SO42-

Na+

?Org. Process Res. Dev., 2017, 21,1355–1370

COSMOtherm

BP-TZVPD-FINE 2016

Dihydrated Na+, monohydrated SO42-

Water content in the organic phase

y = x

Experimental

Pre

dic

ted

Conditions:

• 35°C

• 14% w/w sodium sulfate (1 molal)

• 33-100% v/v MeTHF in DME

Org. Process Res. Dev., 2017, 21,1355–1370

COSMOtherm predictions:

• Correct trend

• Water in the organic phase

overpredicted by a factor of ~2

Salting out effect (Dm)

y = x

Experimental

Pre

dic

ted

Dm(Exp)

% vol

MeTHF

in DMECOSMOtherm predictions:

• Correct trend

• Salting out overpredicted

by a factor of ~2.3.

Org. Process Res. Dev., 2017, 21,1355–1370

wt%

Na2SO4

Change of Dm at 35 °C with wt% Na2SO4 (aqueous phase)

and vol% 2-MeTHF (organic phase). Vorg/Vaq = 2.

Oiling out (SLLE behaviour)

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Why it is important:

• Oil phase is often a good solvent for impurities, which will lower the purity of the final product

• May stick to vessel walls/agitator/probes

• Slows crystallisation rate as the meta-stable liquid phase hinders primary and secondary nucleation

• Uncontrollable morphology of crystals

What it is:

“A liquid-liquid phase boundary below the liquidus, but inside

the metastable zone, where a supersaturated solution may

be prone to liquid-liquid phase separation before the onset of

crystal formation”Davey et al, CHEM. COMMUN. , 2003, 698–699

“From a thermodynamic point of view, oiling out is supposed

to be caused by a superposition of liquid–liquid demixing

and solid–liquid phase equilibrium (solubility curve).”Sadowski et al, Journal of Crystal Growth 2008, 310, 4163– 4168

Thank you!

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AstraZeneca

David Buttar

David Hose

Lucie Miller-Potucka

Anna Jawor-Baczinska

Andy Phillips

Simon Yates

Simon Black

Mark Graham

Emerging Technologies Consortium

Solubility Working Group

Yuriy Abramov (Pfizer)

Jacob Albrecht (BMS)

Rahul Sangodkar (Amgen)

Mike Lovette (Amgen)

Frank Ricci (BI)

Jeff Tan (Lilly)

Alex Chin (Merck)

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Cambridge, CB2 0AA, UK, T: +44(0)203 749 5000, www.astrazeneca.com

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