anna jawor-baczynska, jan sefcik

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