Case Studies in Crystallisation and Polymorphism March 2018 PDF

Scientific Update Webinar
Case Studies in Crystallisation and

Polymorphism
March, 13, 2018
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2
Agenda
Introduction
Bosutinib monohydrate vs. hexahydrate
Crystallisation design to remove an unexpected impurity
Efavirenz analogue, polymorphs and solvates
ASP3026, polymorph control
Oratinib, dealing with a solvent removal problem
Liquid crystal example, impurity removal.
Crystallinity control for product stability
Conclusions
3
Solid Forms
Amorphous
Crystalline
Hydrate
Solvate
Salts
Co-crystal
Polymorphs of the above
4
Why Use Crystallisation?
Purify the compound

Reject impurities
Get the desired form (hydrate, salt, polymorph
etc).
Set the physical form of the compound.
Particle morphology
Particle size distribution
Ease of handling
Flowability
5
Intermediates vs Active Ingredients
Active Ingredient
Minimise
Insoluble residues
Impurities, organic, inorganic, genotoxic etc
Residual solvent
Quality more important than yield
Intermediate
Yield often more important than absolute quality
Aiming for large crystals to facilitate solids
handling
Physical properties relatively unimportant
6
Solubility Curve and Metastable Zone
7
Polymorphism
Defined as “the ability of a compound to exist in

more than one crystal form”
We are dealing with different unit cells
Internal arrangement of molecules is different
Therefore different thermodynamic properties
Can arise from
Molecule’s ability to change conformation
Molecules stacking together in different ways
Different tautomers of the molecule (desmotropes)
Different hydrogen bonding patterns
8
How Many Forms Will You Find?
35
30
25
Number of
20
compounds
15
10
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Number of forms
G.P. Stahly (SSCI), 22nd SCI Process Development Symposium,
Cambridge, Dec 2004; Cryst. Gr. Des., 2007, 7, 1007 – 1026.
9
How Many Forms?
CONHMe
H
N S
Axitinib
N InlytaTM
Anhydrous polymorphs 5
Hydrates 2
Solvates 64
A.M. Campeta et al (Pfizer), J. Pharm. Sci., 2010, 99, 3874;
B.P. Chekal, et al (Pfizer), Org. Proc. Res. Dev., 2009, 13, 1327.
10
Bosutinib Monohydrate (Bosulif)
Cl Cl Cl Cl
Me Me
N N
MeO NH MeO NH
MeO NC POCl3 MeO CN

N O N
sulpholane
N N
H
Aqueous quench followed by basification with KOH gives

Bosutinib hexahydrate (6.H2O)
Recrystallisation from IPA - water gives Bosutinib
dihydrate mono isopropanol solvate (2.H2O - 1.i-PrOH)
Slurrying in hot water gives the desired monohydrate form
(1.H2O).
Slurry to slurry transformation gives wide particle size
distribution.
11 G.J. Withbroe et al (Pfizer), Org. Proc. Res. Dev., 2013, 17, 500.
Solvent Screening and Solubility Studies
Bosutinib forms solvates with MeCN, THF, DCM,

CHCl3, 1,4-dioxane and alcohols.
MeOH EtOH, IPA, n-PrOH, n-BuOH, i-BuOH, t-AmOH, 2-
methoxyethanol.
Ketones and esters give the monohydrate or the
hexahydrate depending on the water content of
the system.
Ideally the same solvent can be used for product
extraction and crystallisation.
Monohydrate vs. Hexahydrate
Solvent systems that Solvent systems that

give the monohydrate: give the hexahydrate:
EtOAc Acetone / H2O (80:20)
i-PrOAc Acetone / H2O (20:80)
n-PrOAc, MEK / H2O (90:10)
n-BuOAc CH3CN / H2O (80:20)
Acetone, CH3CN / H2O (20:80)
MEK MeOH / H2O (20:80)
MIBK* EtOH / H2O (20:80)
Toluene n-PrOH / H2O (20:80)
n-Heptane i-PrOH / H2O (20:80)
Xylene EtOAc / H2O*
*saturated with H2O i-PrOAc / H2O*
Critical Water Activity
Solvent Choice
Esters ruled out because of concerns over

hydrolysis arising from the basic quench mixture
Product has good solubility in MEK and acetone
but these are water miscible
Soluble in hot MIBK, so ….
MIBK chosen for an extractive work up and
subsequent crystallisation.
Optimising the Work Up and Isolation
Reaction mixture after the aqueous quench is

adjusted to pH 3-5 with aq KOH at 75-80°C
MIBK is added and sulpholane is extracted in to
the organic layer.
Aqueous layer is basified to pH 10 with aq KOH
Product is extracted in to MIBK at 75-80°C
MIBK solution concentrated to 4 volumes
1-2% Water added, followed by seeding at 60-
65°C
Optimisation of MIBK Extraction /
Crystallisation
Solubility curves generated for MIBK and MIBK - water
mixtures
Water levels up to 2% will produce the desired
monohydrate
Higher levels of water give mixtures of monohydrate and
hexahydrate.
Azeotropic water removal to 4L / kg MIBK reduces water
content to <0.3%.
An accurate water charge of 1-2% and seeding with
monohydrate at 60-65ºC leads to crystallisation of the
desired monohydrate.
This gives 75-82% yield, with >99.5 area % purity.
Monohdyrate Solubility in MIBK
Crystal Morphology
A B
Original process, from slurry to New MIBK extraction, seeded
slurry transformation crystallisation work up and
of hexahydrate to isolation
monohydrate
Pharma Intermediate Purification
O O O
I
NH NH NH
N O NHSO2Me N O N O
+
Reactant B
t-Bu t-Bu t-Bu
OMe H OMe O
Reactant A Intermediate C Impurity D

NHSO2Me
Sonagashira coupling NHSO2Me
Pilot plant run to produce 48kg of Intermediate C.

A new Impurity D formed at 3.5 area % by hplc during
work up.
Thought to be caused by the presence of acid combined
with high temperature.
Solution held as 50 mg/ml (20 ml/g) solution in THF.
20 A.M. Czyzewski et al (AbbVie), Org. Proc. Res. Dev., 2017, 21, 1493.
Initial Studies
Taking the solution through the existing

crystallisation process gave, ultimately, API
containing 1.7 area % Impurity D.
Alternative crystallisation solvents and solvent
mixtures were evaluated (MeOH, H2O, IPA, ACN,
Me2O, 2-MeTHF, PhCH3, MTBE, DMAc).
Salts were also investigated.
Most promising option was an antisolvent
crystallisation:
Distil to 6 ml/g in THF, add 24 ml/g of antisolvent.
This still gave unacceptable levels of impurity D.
Crystallisation Dynamics
Impurity D solubility is always lower than that of

Intermediate C.
At 6 ml/g in THF Intermediate C begins to
crystallise out as a THF solvate (Form II), Impurity
D remains in solution.
At the end of the antisolvent addition C
transforms over to anhydrous Form I.
After antisolvent addition D is still in solution.
After a few hours D begins to crystallise.
The Form II to Form I transition takes place well
before D starts to crystallise.
Possible Options
Isolate the THF solvate.

Yield <50%
Find an additive that changes the crystallisation kinetics of
Impurity D modified so that nucleation of D is further
retarded.
Polymers are known to impact crystallisation processes
and crystal properties.
Hydroxypropylmethyl cellulose and Copvidone (Kollidon
VA 64) both work.
Addition of Copvidone led to appearance of Form III, a
new solvate, and the thermodynamically most stable form
in this solvent system.
Crystallisation Development
Aim: delay the onset of Impurity D crystallisation by at

least 16 hours after completion of the antisolvent.
IPA chosen as antisolvent, 2 hour addition at 0°C chosen
with varying levels of Copvidone (0.1-1.2 %, w/w based on
D).
A minimum Copvidone loading of 1.5 wt % is required to
produce Intermediate C with <0.2% Impurity D.
Copvidone Intermediate C Intermediate D

Solubility at 0°C Solubility at 0°C
0.0% (w/w) 0.11% (w/w) 0.02% (w/w)
0.3% (w/w) 0.12% (w/w) 0.05% (w/w)
Effect of Copvidone Loading
Analytical Development
An NMR assay was developed to quantify residual

Copvidone in Intermediate C
The method can detect Copvidone down to
<0.1% (w/w).
All lab batches showed ~0.5% w/w Copvidone.
This can be further reduced via slurrying the solid
in 20 vols IPA at 60°C, followed by cooling to
20°C.
Final level Copvidone level <0.1% (w/w).
Pilot Plant Implementation
3kg Copvidone (~3% based on Intermediate C) was added

to the batch.
Distillation reduced THF from 20 volumes to 6 volumes.
Cooled to 0°C, and 24 volumes of IPA were added over 2
hours.
Stirred at 0°C for 2 hours and then filtered, well within the
16 hour timeframe.
The isolated wet cake was reslurried in 20 volumes IPA to
give Form III crystals of C containing <0.1% (w/w) Impurity
D, and <0.1% (w/w) Copvidone.
Process Understanding
(a) Intermediate C concentration in solution (b) Impurity D concentration in solution
Effect of Seeding on Impurity D
Crystallisation
(a) Without Copvidone (b) With Copvidone
Efavirenz Analogue
F3C EITHER F3C
Cl TFA - H2O, Cl
N 18°C, 1 hour NH
OR HCO2H
N O 60°C, 2-3 hours N O
H 80-85% H
Form I discovered via sublimation, mpt 181ºC

Final deprotection carried in neat HCO2H, followed by
crystallisation from toluene-heptane.
This gives a mixed toluene-heptane solvate which
undergoes thermal conversion to Form 1 with a variable
level of amorphous material
30 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

Efavirenz Analogue
Recrystallisation of crude API from methanol affords a

stoichiometric methanol solvate.
Designated Form II
Drying Form II at 90ºC for 4 hours followed by 3 hrs at
120ºC gives Form I.
29 Batches prepared up to 150kg scale.
Batch 30…
Samples melt at 174ºC.
Designated Form III
Now, only able to make Form I via prolonged heating at
melt temperatures of Form III.

Form I DSC

Form III to Form I Conversion
33
Form III to Form I Conversion:
Heating at 10ºC / min

Form III to Form I Conversion:
Heating at 2ºC / min

Efavirenz Analogue
Form I Form III

Efavirenz Analogue
API forms solvates with MeOH, EtOH, IPA,

Form I and Form III are the only anhydrate forms
known.
Forms I and III are enantiotropic polymorphs.
The transition temperature is inferred to be
between 120-174ºC
At ambient temperatures (far from the transition
temperature) Form III is likely to be significantly
more stable than Form I

Efavirenz Analogue
Form I Form III
Form I Enantiotropic by BHM

mpt 181C Transition temp
ΔHm 19.10 kJmol-1 between 120-174C
Form III Form I converts to Form
III at 120C mpt 174C
Form I converts to Form ΔHm 20.80 kJmol-1
III at 40C / 75% RH

Efavirenz Analogue
Solvent screen undertaken to find suitable

conditions for direct crystallisation of Form III
n-Propanol chosen with water as anti-solvent.
5 wt % of Form III seeds used.
In one batch needle like crystals appeared which
were found to be an n-propanol solvate.
PVM studies showed the formation of a quasi-
emulsion phase with larger quantities of API in the
n-propanol phase

Quasi-Emulsion Phase

Phase Behaviour

Developing the Crystallisation
Protocol 1: seed at 45ºC with 5 wt % seeds as a slurry in n-

PrOH-H2O
Better but some quasi-emulsion behaviour observed
Protocol 2: seeding temperature lowered to 30ºC.
No emulsion formation, but n-PrOH solvate observed during
crystallisation but this converted to Form III on addition of water
Scaled up to 300kg / 1,000L scale.
Protocol 3: solution of API in n-PrOH slowly added to a
slurry of Form III seeds in water
Under these conditions Form III is the stable form throughout the
crystallisation
Some agglomeration was observed but this could be overcome by
intense mixing and by sonication

Agglomeration Behaviour

Formulation
Originally Form I formulated as 50mg strength

tablets
Accelerated stability studies showed complete
conversion to Form III at 40ºC, 75% RH.
Formulation modified to accommodate Form III
and this was found to be equivalent to Form I
through a relative bioavailability study in humans.
No difference in the in vivo performance of the
two forms.

ASP3026
CH3
N
N
N N
N N N
H H
S O OCH3
ASP3026
O
In early development a mixture of forms A01 and

A02 was obtained
5 Polymorphs A01 – A05 have been found and
one hydrate
Thermodynamic stability is A05 < A01 < A02 <
A03 < A04 at room temperature.
45 K. Takeguchi et al (Astellas), Org. Proc. Res. Dev., 2016, 20, 970.
Polymorph Landscape
A03 and A04 are monotropic polymorphs with

A04 always more stable.
A03 and A04 are examples of concomitant
polymorphism, where several polymorphs of one
compound nucleate and grow simultaneously
A04 is the desired form for formulation but the
synthesis produces form A02.
A solvent mediated polymorphic transformation
(SMPT) of A02 to A04 was studied with online
Raman spectroscopy using a scaled down version
of the pilot plant vessel.

Solvent Selection
Hansen solubility values
Including one-component values
Solvent    Dipole Dielectric  d p h
Moment constant (MPa1/ (MPa1/ (MPa1/ (MPa1/
2) 2) 2) 2)
EtOH 0.37 0.48 0.54 1.69 24.85 26.0 15.8 8.8 19.4
IPA 0.33 0.56 0.48 1.56 19.26 23.5 15.8 6.1 16.4
Acetone 0.04 0.49 0.71 2.88 20.49 20.3 15.5 10.4 7.0
MEK 0 0.51 0.67 2.78 18.25 19.0 16.0 9.0 5.1
MIBK 0 0.51 0.65 2.81 12.89 17.2 15.3 6.1 4.1
EtOAc 0 0.45 0.55 1.78 5.99 18.6 15.8 5.3 7.2
H2O 1.17 0.47 1.09 1.87 78.36 47.9 15.5 16.0 42.3

Raman Spectra of A02, A03, and A04

Time Dependence of 1240cm-1 Peak in MEK,
Acetone and EtOH
Induction time = time from addition of AS3026 to the start

of the polymorph transformation based on peak intensity.
Weight % of A04 by Raman
(a) based on the

peak at 833 cm-1
(b) based on the

peak at 1310 cm-1

SMPT at 25°C
Solvent A04 solubility Induction A03 : A04 A03 : A04

time Raman DSC
EtOH 3.1 g/L 427.5 hr 94:6 91.3:8.7
IPA 0.8 g/L >768 hr - -
Acetone 4.0 g/L 66.4 hr 62:38 65.1:34.9
MEK 5.8 g/L 39.6 hr 45:55 45.9:54.1
MIBK 3.2 g/L 83.0 hr 94:6 89.6:10.4
EtOAc 3.7 g/L 159-216 hr 100:0 97.5:2.5
Acetone : H2O 4.5 g/L >330 hr - -
EtOH : H2O 5.4 g/L >567 hr - -

SMPT at 50°C
Solvent A04 solubility Induction A03 : A04 A03 : A04

time Raman DSC
EtOH 9.7 g/L 10.7 hr 10:90 0:100
IPA 7.8 g/L 39.2 hr 94:6 0:100
Acetone 10.2 g/L 5.8 hr 4:96 0:100
MEK 16.6 g/L 1.4 hr 1:99 0:100
MIBK 8.3 g/L 8.4 hr 2:98 0:100
EtOAc 9.6 g/L 2.7 hr 5:95 0:100
Acetone : H2O 11.0 g/L 15.1 hr 5:95 0:100
EtOH : H2O 15.9 g/L 9.2 hr 10:90 0:100

Solvent Comparison: 25C vs. 50C
Solvent Temp (°C) A04 Induction A03 : A04 A03 : A04

solubility time Raman DSC
EtOH 25 9.7 g/L 10.7 hr 10:90 0:100
50 3.1 g/L 427.5 hr 94:6 91.3:8.7
IPA 25 7.8 g/L 39.2 hr 94:6 91.3:8.7
50 0.8 g/L >768 hr - -
Acetone 25 10.2 g/L 5.8 hr 4:96 0:100
50 4.0 g/L 66.4 hr 62:38 65.1:34.9
MEK 25 16.6 g/L 1.4 hr 1:99 0:100
50 5.8 g/L 39.6 hr 45:55 45.9:54.1
53
Solvent Comparison: 25C vs. 50C
Solvent Temp (°C) A04 Induction A03 : A04 A03 : A04

solubility time Raman DSC
MIBK 25 8.3 g/L 8.4 hr 2:98 0:100
50 3.2 g/L 83.0 hr 94:6 89.6:10.4
EtOAc 25 9.6 g/L 2.7 hr 5:95 0:100
50 3.7 g/L 159-216 hr 100:0 97.5:2.5
Acetone : H2O 25 11.0 g/L 15.1 hr 5:95 0:100
50 4.5 g/L >330 hr - -
EtOH : H2O 25 15.9 g/L 9.2 hr 10:90 0:100
50 5.4 g/L >567 hr - -
54
Conclusions
The induction time is shortest in ketone and ester

solvents, although the exact solvent order
changes with temperature
At 50°C: MEK > EtOAc > Acetone > MIBK > EtOH-H2O >
EtOH > Acetone-H2O > IPA
At 25°C: MEK > Acetone > MIBK > EtOAc > EtOH
A02 can be converted to A04 at higher
temperature using highly polar non-H-bond-
donating solvents
A02 can be converted to A03 at low temperature
using low polarity or H-bond-donating solvents.

Product Purity
Temp Yield Purity Imp 1 Imp 2 Imp 3 Imp 4 Form ROI

Initial 98.9% 0.08% 0.15% 0.22% 0.07% A02
Acetone 50°C 82% 99.5% 0.04% 0.03% 0.03% 0.05% A04 0.47%
MEK 50°C 76% 99.6% 0.03% 0.01% 0.01% 0.04% A04 0.56%
Ace-H2O 50°C 88% 99.4% 0.01% 0.02% 0.02% 0.07% A04 <0.1%
ROI spec: 0.2%

So, ultimately acetone-water was chosen for the
SMPT
Concern about possible hydrate contamination

Solubility Curves in Acetone-H2O

Progress of the Transition
Given the lengthy induction time observed in the lab – 15 hours, the
SMPT was seeded with A04 on scale.
Changing Crystal Habit

Increasing Chord Length

A04 Ratio vs. Induction Time

Oratinib
CO2K CO2H
N N
H H
aq HCl
O O
IPA - H2O
N N
H H
API, coloured, light sensitive

Crystallisation process not robust
Variable amounts of IPA, often exceeding the ICH
limit of 5,000 ppm
Variable particle size distribution
H. Sato et al (Taiho Pharmaceuticals), Org. Proc. Res. Dev., 2015, 19, 1655.
62
DoE Study of Crystallisation
8 Factors studied in a quarter factorial design,

with 2 centre points
Amount of solvent 16.4, 21.4, 26.4 vols
Solvent ratio 31, 41, 51: IPA/H2O
Temperature 40, 50, 60°C
Agitation speed 80, 160, 240 rpm
HCl concentration 7, 12, 17%
Duration of HCl addition 1, 2, 3 hours
Final pH 1, 3, 5
Additional agitation 0.25, 1, 1.75 hours
63
Variation in Particle Size
16.4 vols, 31% IPA/H2O, 40°C, 26.4 vols, 51% IPA/H2O, 60°C,
80 rpm, 17% HCl, 3 hour 80 rpm, 7% HCl, 3 hour
addition, to pH 5, 0.25 hour stir addition to pH 1, 0.25 hour stir
out out
64
Key Factors for Residual IPA
Temperature > Amount of solvent > Agitation speed >

Duration of HCl addition > Solvent ratio
The high setting of each factor is preferred
65
Key Factors for PSD
Solvent ratio  Temperature > Duration of HCl addition
66
Further Optimisation
Unimportant factors omitted in next design

HCl concentration, final pH, and stir out time
A further 16 experiment plus 2 centre points,
were carried out to upgrade to a response surface
analysis
Temperature, solvent volume, solvent ratio, agitation
speed, duration of HCl addition
Aim to reduce residual IPA levels and obtain a PSD
similar to original API
67
Ranges Expanded
Factor Original range Expanded range

Temperature 40-60°C 40-80°C
Solvent ratio 31-51% 11-51%
Duration of HCl addition 1-3 hours 0.25-3 hours
Amount of solvent 16.4-26.4 volumes 16.4-36.4 volumes
Agitation speed 80-240 rpm 40-280 rpm
Higher temperature gives less IPA, but larger particles

Lower solvent ratio gives smaller particles
Shorter HCl addition gives smaller particles
Larger solvent volume gives less IPA
Although agitation has no specific effect it was expanded
at both ends
68
Results
Impurity levels increase at higher temperature, 80°C or

lower solvent ratio (11% IPA/H2O)
Optimum conditions calculated to be:
Temperature 67°C
Solvent ratio 22% IPA/H2O
Duration of HCl addition 2 hours
Volumes of solvent 36 volumes
Agitation speed 200 rpm
Predicted to give:
Residual IPA 2223 ± 1210 ppm
PSD D10 3.2 ± 0.8 m
D50 4.9 ± 1.2 m
D90 7.4 ± 2.0 m
69
Verification Experiments
Lab scale Actual Predicted

Residual IPA 2138 ppm 1013-3433 ppm
D10 1.6 m 2.4-4.0 m
D50 2.7 m 3.7-6.1 m
D90 4.2 m 5.4-9.4 m
Model improved by adding this data gave new conditions:
Temperature 67°C changed to 70°C
Solvent ratio 22% changed to 25% IPA/H2O
Duration of HCl addition 2 hours no change
Volumes of solvent 36 volumes no change
Agitation speed 200 rpm no change
70
Second Verification Experiments
Parameter Predicted Actual 1 Actual 2

Residual IPA 1386-3252 ppm 2622 ppm 2297 ppm
D10 2.5-4.1 m 3.5 m 3.4 m
D50 3.9-6.1 m 5.6 m 6.0 m
D90 5.7-9.3 m 8.6 m 9.7 m
Yield 94.7% 95.2%
Process successfully scaled up to produce 3kg of

API
71
“Design Space”
72 H. Sato et al (Taiho Pharmaceuticals), Org. Proc. Res. Dev., 2015, 19, 1655.
Liquid Crystal Intermediate
H
1. Hydrogenation
R X R X
2. Isomerisation
3. Work Up H
4. Purification
R: alkyl chain R
X
X: polar group
D. Maillard (Merck), The 38th International Conference

73 on Organic Process R&D, Stockholm, September 2017.
Liquid Crystal Intermediate
H
1. Hydrogenation
R X R X
2. Isomerisation
3. Work Up H
4. Purification
R: alkyl chain R
X
X: polar group
Impurities typically need to be

controlled to ppm levels.
R X
One production batch contained Impurity A
1940 ppm Impurity A and 410 ppm

Impurity B. R X
Standard crystallisation did not

reduce the levels of Impurities A & B.
Impurity B

Preliminary Studies
Crystallisation process: cool a 20 wt % solution to 0°C

(cooling ramp not critical), filter at 0°C and wash with cold
IPA.
Alternative solvent screening:

Effect of Concentration
No change in impurity removal going from 15 wt% to 30 wt% (cooling

ramp 0.5°C per min to 0°C, no age time, no washing).
Yield low at 15 wt%, caking and fouling observed at 30 wt%.
Faster cooling ramp (1°C per min) does not affect purity but does
cause caking and fouling effects.
Further Investigations
Seeding with pure material gives a slightly better

depletion of A & B, but only at temperatures >
30°C.
On the plant (4 m3 reactor) the only deviation
from the desired process was occasional delays in
filtering batches leading to a long aging time.
In addition the filtration time would normally take
7-8 centrifuge runs at 90-100kg per run.

The Effect of Aging Time
Temp Product (%) Imp A (ppm) Imp B (ppm) Comments

15 99.87 420 100 During cooling, in process
-1 99.85 430 110 No aging before filtration
-1 99.83 440 130 18 hour age time before filtration
-1 99.61 1760 420 24 hour age time before filtration,
“sludgy” suspension.
-1 99.51 1620 430 43 hour age + washing, very fine
crystals.

The Effect of Aging Time
Temp Product (%) Imp A (ppm) Imp B (ppm) Comments

15 99.87 420 100 During cooling, in process sample
-1 99.85 430 110 No aging before filtration
-1 99.61 1760 420 24 hour age time before filtration,
-1 99.51 1620 430 43 hour age + washing, very fine
crystals.
In the lab a standard 18 hour aging time was used.

After 24 hours a “sludgy” suspension was observed, giving very fine
crystals with long filtration and washing time.
These crystals have essentially the same composition as the starting
material.
In Process Analysis
Constant jacket
temperature
maintained.
An internal
temperature rise of
1°C is observed.
The chord length
distribution shows
a sudden decrease
from 22 m to 6-7
m.

Online Tracking of Chord Length
200
100
The chord length collapses over

~ 1 hour. 50
The good crystals convert to fine
crystals with inclusion /
entrapment of Impurities A & B. Before After
transition transition

Confirmation of Polymorphic Transformation
Offline Raman analysis:
Heating up and recooling has no effect so once the

transition has occurred it is irreversible.

Investigation of the
Polymorph Transition
Concn (wt %) Tend (°C) Aging time (hrs) Transition Time for
transition (hrs)
20 0 60 Y 21.5
20 15 60 Y 23.5
20 23 86 Y 24
20 27 115 N -
20 30 76 N -
25 30 60 N -
So the critical transition temperature is between 23-27°C.

Investigation of the
Polymorph Transition
Concn (wt %) Tend (°C) Aging time (hrs) Transition Time for
transition (hrs)
20 0 60 Y 21.5
20 15 60 Y 23.5
20 23 86 Y 24
20 27 115 N -
20 30 76 N -
25 30 60 N -
30 29.5 69 N -
30 26.7 24 N -
30 24.6 72 N -
30 22.5 72 Y 24
30 29.5 50 N -

Graphical Representation of the
Transition

Recommendations for Production
If Impurities A & B are formed during the

hydrogenation, the crystallisation mixture must be
kept above 24°C.
The final product isolation / filtration temperature
must be >24°C in order to effectively purge
Impurities A & B.
This means settling for a lower yield to get the
required purity.

Crystallinity Control for
Product Stability
Scale-up leads to
poor crystallinity
Laboratory scale process Upon scale-up crystal

produced high-quality quality and size changed,
crystals purity not impacted
Simple, anti-solvent process Bulk drug batches started
failing long term stability
with minimal controls for
“ease of operability” Process sent back to the
lab - delay in transfer to
Crystal size consistent supplier
87 S. Deshmukh (Wyeth), Sci Update PAT Conference, Milan June, 2006.

DSC Profiles Show
Differences in Crystallinity
Onset temperature
Heat of fusion

Quantitation of Crystallinity
Used to Predict “Z” Stability
Differential Scanning Calorimetry
Quantitative method for measuring the degree of crystallinity using
onset temperature/ heat of fusion
70 163
162.5
60 y = 0.0875x + 153.69 162

2
R = 0.9787
161.5
50
161
40 160.5
Heat of fusion
160
30 y = 0.6049x - 1.9884
2 159.5
R = 0.996
20
Onset temperature, °C Desirable 159
Crystallinity
158.5
10
158
0 157.5
45 50 55 60 65 70 75 80 85 90 95 100 105 110

Crystallinity, %

Relation Between Crystallinity
and Shelf Life
Design space for “Z” storage
“Z” shelf life

Experimental Design (DoE)
Construct Experiment Design

Nucleation induction time
Rate of antisolvent addition
Hold time after antisolvent addition Determine Important Factors
Location of antisolvent addition point 4 factors
Mixing speed during antisolvent addition
Mixing speed after antisolvent addition 3 levels
Solvent B: antisolvent ratio 12 runs
Solvent A content in amorphous API
Impurity level in crude API
Total factors = 9
Test Modified Process Optimize Factors

Scale up runs

Effect of Mixing Speed on Crystallinity*
Investigation: CCI crystallization-6 (MLR)
Induction time vs acetone content

4D Contour of crystallinity
Time for heptane addn = 135

Mixing
speed 160 speed 160 RPMFigure 7.6B, mixing 580 RPM
Figure 7.6A, mixing RPM speed 580 RPM
Low
•Model identified operating region
for high
Figure crystallinity
7.6: Response surface model for crystallinity
MOD D E 7 - 12/21/2005 2:33:39 PM MOD D E 7 - 12/21/2005 2:35:56 PM
as a function of acetone content and induction time

at•Mixing speed
constant heptane did time
addition notofshow
135 min.a
High significant impact on crystal quality
*Crystallinity determined by DSC

and particle size measurement
1000
Figure 7.6C, mixing RPM
speed 1000 RPM
MOD D E 7 - 12/21/2005 2:37:44 PM

Crystallisation Trajectory Established
Induction time = nucleation time + aging time

8000
Counts
(FBRM) 11 v% solvent A, 0.2h linear AS addn
500 RPM
6000
4000
A/S added
A/S added immediately after
before nucleation
nucleation
2000
A/S added
Aging after aging
0
0 20 40 60 80 100 120 140
Time (min)
Conclusions
The practice of crystallisation is regarded by

chemical engineers as one of the most difficult
unit operations to control and scale-up
We are attempting to exert control over things
which are operating at a molecular level with the
interaction of both kinetic and thermodynamic
effects in a dynamic system with phase changes,
cooling ramps and / or anti-solvent addition
taking place.
The key is understanding – we must be prepared
to invest time and effort in this operation if we are
to gain control
94
Conclusions
All too often development teams spend time and

effort on the chemistry, but then skimp on the
process understanding around crystallisation
……….only paying attention when they hit a
problem!
Early assessment of solid state characteristics is
crucial for the API
Recognition of potential issues for intermediates
is also required…….failure to do so may leave you
without a critical purification stage.
95
Conclusions and Recommendations
Crystallisation of the final product will ALWAYS be

a critical step.
ALWAYS carry out solubility studies to enable a
phase diagram to be constructed.
This will involve more work and variations on the
basic concentration vs temperature diagram for
systems where solvates and / or hydrates and / or
polymorphs can form.
Measure the settling time on a 1 litre scale to
check for possible filtration problems.
96
Solubility Curve and Metastable Zone
97
A Big Thank You to Our Sponsor
98

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Scientific Update Webinar

Case Studies in Crystallisation and

Purify the compound

Defined as “the ability of a compound to exist in

MeO NC POCl3 MeO CN

Aqueous quench followed by basification with KOH gives

Bosutinib forms solvates with MeCN, THF, DCM,

Solvent systems that Solvent systems that

Esters ruled out because of concerns over

Reaction mixture after the aqueous quench is

t-Bu t-Bu t-Bu

Reactant A Intermediate C Impurity D

Sonagashira coupling NHSO2Me

Pilot plant run to produce 48kg of Intermediate C.

Taking the solution through the existing

Impurity D solubility is always lower than that of

Isolate the THF solvate.

Aim: delay the onset of Impurity D crystallisation by at

Copvidone Intermediate C Intermediate D

An NMR assay was developed to quantify residual

3kg Copvidone (~3% based on Intermediate C) was added

(a) Intermediate C concentration in solution (b) Impurity D concentration in solution

(a) Without Copvidone (b) With Copvidone

F3C EITHER F3C

Form I discovered via sublimation, mpt 181ºC

30 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

Recrystallisation of crude API from methanol affords a

31 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

32 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

34 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

35 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

Form I Form III

36 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

API forms solvates with MeOH, EtOH, IPA,

37 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

Form I Form III

Form I Enantiotropic by BHM

38 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

Solvent screen undertaken to find suitable

39 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

40 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

41 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

Protocol 1: seed at 45ºC with 5 wt % seeds as a slurry in n-

42 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

43 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

Originally Form I formulated as 50mg strength

44 S. Desikan et al (BMS), Org. Proc. Res. Dev., 2005, 9, 933.

In early development a mixture of forms A01 and

A03 and A04 are monotropic polymorphs with

46 K. Takeguchi et al (Astellas), Org. Proc. Res. Dev., 2016, 20, 970.

47 K. Takeguchi et al (Astellas), Org. Proc. Res. Dev., 2016, 20, 970.

48 K. Takeguchi et al (Astellas), Org. Proc. Res. Dev., 2016, 20, 970.

Induction time = time from addition of AS3026 to the start

(a) based on the

(b) based on the

50 K. Takeguchi et al (Astellas), Org. Proc. Res. Dev., 2016, 20, 970.

Solvent A04 solubility Induction A03 : A04 A03 : A04

51 K. Takeguchi et al (Astellas), Org. Proc. Res. Dev., 2016, 20, 970.

Solvent A04 solubility Induction A03 : A04 A03 : A04

52 K. Takeguchi et al (Astellas), Org. Proc. Res. Dev., 2016, 20, 970.

Solvent Temp (°C) A04 Induction A03 : A04 A03 : A04

Solvent Temp (°C) A04 Induction A03 : A04 A03 : A04

The induction time is shortest in ketone and ester