anna jawor-baczynska, jan sefcik
TRANSCRIPT
References
1 Roger A. Granberg, Ake C. Rasmuson; ‘Solubility of Paracetamol in Binary and Ternary Mixtures of Water+ Acetone + Toluene’, J. Chem. Eng. Data 2000, 45, 478-483.2 H. Hojjati, S. Rohani; ‘Measurement and Prediction of Solubility of Paracetamol in Water-Isopropanol Solution. Part 1. Measurement and Data Analysis’, Organic Process Research&Development
2006, 10, 1101-1109.
Modular test bench for continuous crystallisation
Anna Jawor-Baczynska, Jan Sefcik
Department of Chemical and Process Engineering, University of Strathclyde, Glasgow, Scotland
Project aims
� To better understand the fundamentals of crystal nucleation mechanism of
pharmaceutical compounds under flow conditions
� To design continuous crystal nucleation units which enable to achieve control
over the particles attributes like particles size, yield, polymorphism, purity etc.
using the model pharmaceutical compounds
Crystal nucleation mechanism in cooling crystallisation of glycine
The crucial features of the crystal such as purity, morphology, crystal lattice organisation, size
and size distribution are defined by condition during the earliest stage of crystallisation –
nucleation. To be able to manage / control the process of the crystal formation (especially in
terms of flow), the mechanism of crystals nucleation should be better understood.
Antisolvent crystallisation – nucleation setups
Model compound (paracetamol) – batch screening
0
50
100
150
200
250
300
350
400
450
500
0 10 20 30 40 50 60 70 80 90 100
Water content [mass%]
So
lub
ility
[g
/kg s
olv
en
t]
Acetone - water
Isopropanol - water
69.8 [g/kgsolvent]
80-20 water-IPA
139.2 [g/kgsolvent]
60-40 water-IPA
150.9 [g/kgsolvent]75-25 water-acetone
301.8 [g/kgsolvent]50-50 water-acetone
Antisolvent - water
0
50
100
150
200
250
300
350
400
450
500
0 10 20 30 40 50 60 70 80 90 100
Water content [mass%]
So
lub
ility
[g
/kg s
olv
en
t]
Acetone - water
Isopropanol - water
69.8 [g/kgsolvent]
80-20 water-IPA
139.2 [g/kgsolvent]
60-40 water-IPA
150.9 [g/kgsolvent]75-25 water-acetone
301.8 [g/kgsolvent]50-50 water-acetone
Antisolvent - water
69.8 [g/kgsolvent]
80-20 water-IPA
139.2 [g/kgsolvent]
60-40 water-IPA
69.8 [g/kgsolvent]
80-20 water-IPA
139.2 [g/kgsolvent]
60-40 water-IPA
150.9 [g/kgsolvent]75-25 water-acetone
301.8 [g/kgsolvent]50-50 water-acetone
150.9 [g/kgsolvent]75-25 water-acetone
301.8 [g/kgsolvent]50-50 water-acetone
Antisolvent - water
Acetone/IPA-water
solution of
paracetamol
Paracetamol
crystals
Magnetic stirrer/
Vortex
Rapid additionWater
Acetone/IPA-water
solution of
paracetamol
Paracetamol
crystals
Magnetic stirrer/
Vortex
Rapid additionWater 42.3±12.984 ±3010.1±2.2120 ±36Vortex
46.2 ±16.4140 ±8374.4 ±3.055±20Magnetic mixer
Solid recovery
[%]
Induction time
[s]
Solid recovery
[%]
Induction time
[s]
IPA-Water
Supersaturation 1.50
Acetone-Water
Supersaturation 1.45
42.3±12.984 ±3010.1±2.2120 ±36Vortex
46.2 ±16.4140 ±8374.4 ±3.055±20Magnetic mixer
Solid recovery
[%]
Induction time
[s]
Solid recovery
[%]
Induction time
[s]
IPA-Water
Supersaturation 1.50
Acetone-Water
Supersaturation 1.45
Paracetamol – continuous antisolvent nucleation – setup 1
Paracetamol – continuous antisolvent nucleation – setup 1
FB
RM
pro
be
T-mixer
Magnetic stirrerCollecting vessel
Controlheating/cooling
FB
RM
pro
be
T-mixer
Magnetic stirrerCollecting vessel
Controlheating/cooling
Figure 2. Effect of nanodroplet size on the outcome of nucleation.
Figure 3. Continuous antisolvent crystallisation setups.
Setup 1: pre-mixing of antisolvent and
solution using static mixers (T, X, Y or
vortex) and introducing mixture into a
nucleator with an additional agitation
element and heating jacket (prevent fouling).
The solution containing small microcrystals
is continuously transferred to the crystal
growth unit (tubular crystalliser, OBC etc).
Setup 2: the cold antisolvent is mixed with
(warm) solution in a nucleator with a heating
jacket (prevent fouling). The solution containing
small microcrystals is continuously transferred
to the crystal growth unit (tubular crystalliser,
OBC etc).
Setup 3: the (warm) solution is introduced
into the flowing in tubular nucleator cold
antisolvent. The solution containing small
microcrystals is continuously transferred to
the crystal growth unit.
Our experimental studies have proposed a two-step mechanism for crystal formation in which
crystal nucleation is preceded by formation of disordered molecular assemblies (nanodroplets).
By employing scattering techniques sensitive to the presence of much larger species we were
able to show that dissolution of glycine crystals leads directly to a small but thermodynamically
stable population of ∼250 nm diameter glycine-rich nanodroplets. These small nanodropletswere found not to lie on a successful nucleation pathway. Only when larger nanodroplets (>500
nm) were produced, via mechanical coalescence of the smaller nanospecies was the rate of
nucleation significantly enhanced. It is proposed that productive crystal growth requires
nucleation to occur within a critical-sized solute-rich nanodroplet, i.e. one containing sufficient
mass of concentrated solute. Otherwise the nascent crystals produced from the solute-rich
nanodroplet will be too small to survive exposure to the more dilute surrounding bulk solution
and will simply redissolve (Figure2).
Figure 1. Continuous crystallisation process –pipeline.
Figure 4. Solubility of paracetamol in acetone
/isopropanol – water solvent1,2
Figure 5. Schema of experimental
setup –batch screening.
Figure 6. Microscope image of paracetamol
microcrystals crystallised from acetone/water
solvent a) magnetic mixing, b) vortex.
Table 1. Induction time and solid recovery – batch.
a b
Figure 7. Schema of experimental
setup –continuous nucleation (setup1).
Figure 8. FBRM monitoring of nucleation, a) process-1, b) process-2.
Initial batch screening test were
done using acetone/ isopropanol
water solvents and model compound
(paracetamol) (Figure 4). The results
show strong influence of sample
preparation techniques and the type
of antisolvent in the final crystal size
and the level of agglomeration
(Figure 6).
The continuous antisolvent nucleation
setup with pre-mixing unit (T-mixer)
were used for paracetamol
precipitation form isopropanol/water
solvent (less fouling and
agglomeration in comparison with
acetone/water systems). The
temperature of the nucleator was
controlled and microcrystals
suspension was continuously
withdrawn into collecting vessel using
peristaltic pump. The nucleation
process was monitored using FBRM
(Figure 7).
Antisolvent crystallisation of paracetamol (supersaturation 1.5) using the first configuration not
shown nuclation after 17 minutes (in a continuous process FBRM). But soon after stopping the
continuous withdrawal of nucleai began to appear, and after about 20 minutes steady state was
achieved in batch mode (Figure 8a). As it turned out that the pre-mixing is not sufficient to
induce crystal nucleation the batch mode was used to generate first nucleai. After about 7.5min
the first nucleai was observed and continuous process was started. The nucleator seemed to
obtain a continuous steady state mode after about 9min, but T-mixer blocked after 14min
(Figure 8b).
Conclusions• Higher supersaturation required for larger nucleation rate
• Too large crystals/ nuclei formed – higher supersaturation/shorter residence time
• Static mixer – dissolving blockage problem
• Fouling – heating nucleator walls
• Operation in fully continuous mode (continuous pipe setup)
NUCLEATION PATHS
INDUCED
COALESCENCE
(same solution)
Productive nucleation
Large nanodroplets
d≈≈≈≈500nm
Nucleation
Growth of nuclei
Crystal larger thancritical size
Growth of crystal
Glycine crystal
Small nanodroplets
d≈≈≈≈250nm
Non-productive nucleation
Crystal smaller than
critical size
Dissolution Nucleation
Glycinemolecules/clusters
Growth of nuclei
NUCLEATION PATHS
INDUCED
COALESCENCE
(same solution)
INDUCED
COALESCENCE
(same solution)
Productive nucleation
Large nanodroplets
d≈≈≈≈500nm
Nucleation
Growth of nuclei
Crystal larger thancritical size
Growth of crystal
Glycine crystal
Productive nucleation
Large nanodroplets
d≈≈≈≈500nm
Nucleation
Growth of nuclei
Crystal larger thancritical size
Growth of crystal
Glycine crystal
Small nanodroplets
d≈≈≈≈250nm
Non-productive nucleation
Crystal smaller than
critical size
Dissolution Nucleation
Glycinemolecules/clusters
Growth of nuclei
Small nanodroplets
d≈≈≈≈250nm
Non-productive nucleation
Crystal smaller than
critical size
Dissolution Nucleation
Glycinemolecules/clusters
Growth of nuclei
Mixing
Mixing unit:
• T, X, Y mixers• Vortex mixer
• Kenics mixer
• Confined Impinging
Jet (CIJ)
Nucleation unit:
• Kenics crystalliser
• Oscillatory Baffled
Crystalliser (OBC)
• Ultrasonic crystalliser
• Coflore crystalliser
• Tubular crystalliser
• Oscillatory Baffled
Crystalliser (OBC)• Stirred tank
PROJECT AIM
Nucleation GrowthMixing Nucleation GrowthMixing
CONTINUOUS CRYSTALLISATION
Nucleation GrowthMixing
Mixing unit:
• T, X, Y mixers• Vortex mixer
• Kenics mixer
• Confined Impinging
Jet (CIJ)
Nucleation unit:
• Kenics crystalliser
• Oscillatory Baffled
Crystalliser (OBC)
• Ultrasonic crystalliser
• Coflore crystalliser
Growth unit:
•• Oscillatory Baffled
•
PROJECT AIM
Nucleation GrowthMixing Nucleation GrowthMixing
CONTINUOUS CRYSTALLISATION
Nucleation Growth
Nucleator
MixingGrowth unit
Continuous
withdrawal
Static mixers:
� T, X, Y-mixers,
� Vortex etc.
Heating/Cooling
jacket
� Tubular crystalliser,� Oscillatory Baffled Crystalliser (OBC) etc.
Nucleator
MixingGrowth unit
Continuous
withdrawal
Static mixers:
� T, X, Y-mixers,
� Vortex etc.
Heating/Cooling
jacket
� Tubular crystalliser,� Oscillatory Baffled Crystalliser (OBC) etc.
Mixer/Nucleator
Cold antisolvent
Growth unit
Heating/Cooling
jacket
(Warm)solution
� Tubular crystalliser,� Oscillatory Baffled Crystalliser (OBC) etc.
Mixer/Nucleator
Cold antisolvent
Growth unit
Heating/Cooling
jacket
(Warm)solution
� Tubular crystalliser,� Oscillatory Baffled Crystalliser (OBC) etc.
0
1000
2000
3000
4000
5000
6000
0 2 4 6 8 10 12 14 16 18 20 22 24Time [min]
Co
un
ts /
se
c
Counts/sec (1-10um)
Counts/sec (10-25um)
Counts/sec (23.3-100um)
Counts/sec (100-251.2um)
Counts/sec (251.2-1000um)
T-mixing start
(7.5min)
T-mixer blocked
(13.5min)Batch
Continuous
Batch
0
1000
2000
3000
4000
5000
6000
0 2 4 6 8 10 12 14 16 18 20 22 24Time [min]
Co
un
ts /
sec
Counts/sec (1-10um)
Counts/sec (10-25um)
Counts/sec (23.3-100um)
Counts/sec (100-251.2um)
Counts/sec (251.2-1000um)
T-mixing start
(7.5min)
T-mixer blocked
(13.5min)Batch
Continuous
Batch
Residence Time: 60secTotal flow rate: 100ml/min
Jacket temp: 20°CBulk temp: 20.5°CSupersaturation: 1.50
0
1000
2000
3000
4000
5000
6000
0 2 4 6 8 10 12 14 16 18 20 22 24Time [min]
Co
un
ts /
se
c
Counts/sec (1-10um)
Counts/sec (10-25um)
Counts/sec (23.3-100um)
Counts/sec (100-251.2um)
Counts/sec (251.2-1000um)
T-mixing start
(7.5min)
T-mixer blocked
(13.5min)Batch
Continuous
Batch
0
1000
2000
3000
4000
5000
6000
0 2 4 6 8 10 12 14 16 18 20 22 24Time [min]
Co
un
ts /
sec
Counts/sec (1-10um)
Counts/sec (10-25um)
Counts/sec (23.3-100um)
Counts/sec (100-251.2um)
Counts/sec (251.2-1000um)
T-mixing start
(7.5min)
T-mixer blocked
(13.5min)Batch
Continuous
Batch
Residence Time: 60secTotal flow rate: 100ml/min
Jacket temp: 20°CBulk temp: 20.5°CSupersaturation: 1.50
0
500
1000
1500
2000
2500
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30Time [min]
Counts
/ s
ec
Counts/sec (1-10um)
Counts/sec (10-25.1um)
Counts/sec( 23.3-100um)
Counts/sec (100-251.2um)
Counts/sec (251.2-1000um)
Stop T-mixing
Continuous
Batch
Residence Time: 60secTotal flow rate: 100ml/min
Jacket temp: 20°CBulk temp: 20.5°C
Supersatutration: 1.50
0
500
1000
1500
2000
2500
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30Time [min]
Counts
/ s
ec
Counts/sec (1-10um)
Counts/sec (10-25.1um)
Counts/sec( 23.3-100um)
Counts/sec (100-251.2um)
Counts/sec (251.2-1000um)
Stop T-mixing
Continuous
Batch
Residence Time: 60secTotal flow rate: 100ml/min
Jacket temp: 20°CBulk temp: 20.5°C
Supersatutration: 1.50
Continuous
withdrawal
Mixer/Nucleator
Cold antisolvent
Growth unit
Heating/Cooling
jacket
(Warm)solution
� Tubular crystalliser,� Oscillatory Baffled Crystalliser (OBC) etc.
Continuous
withdrawal
Mixer/Nucleator
Cold antisolvent
Growth unit
Heating/Cooling
jacket
(Warm)solution
� Tubular crystalliser,� Oscillatory Baffled Crystalliser (OBC) etc.
69.8 [g/kgsolvent]80-20 water-IPA [%mass]
at 20°C
Water
at 4°C, Flow rate 50g/min
139.2 [g/kgsolvent]60-40 water-IPA [%mass]
at 23°C, Flow rate:50g/min
69.8 [g/kgsolvent]80-20 water-IPA [%mass]
at 20°C
Water
at 4°C, Flow rate 50g/min
139.2 [g/kgsolvent]60-40 water-IPA [%mass]
at 23°C, Flow rate:50g/min