Revealing shapes –particle morphology hints impurity rejection capability during API crystallization

Jochen Schöll

Technobis webinar on 24 SEP 2020

WAG

XLab

MSD Werthenstein BioPharma in Schachen Lucerne

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“Medicine is for the people.It is not for the profits.”

George W. Merck (1950)

Main tasks in pharma crystallization

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Process: • Solvent system• Temperature• Addition rates

• etc…

Typical development challenge: limited amount of API

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and 3 ways to make most out of it:

Miniaturization ParallelizationData-rich

experimentation

Approaches in our lab

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Miniaturization ParallelizationData-rich

experimentation

Unmilled API

Crystallization issues during 1st GMP delivery (1.5 kg API)

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• Solvent switch crystallization (EtOAC→ Toluene) successfully rejected impurities but failed controlling solid form

• Additional recrystallization from MeOH/Water was needed to control the crystal form

• Final micronization step via spiral jet milling yielded 1.5 kg API

Quantiles [µm]

x10 1.4

x50 4.1

x90 8.1

Jet-milled API

Quantiles [µm]

x10 40.2

x50 78.0

x90 152.6

Solvent (pre-)selection with HT data

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Solvent Selection Average [mg/ml] Solvent Selection Average [mg/ml] Solvent Selection Average [mg/ml]

Acetone 90.14 50:50 EtOH:H2O 0.46 2:1 DMF:H2O 8.24

MeCN 50.41 25:75 EtOH:H2O 0.06 1:1 DMF:H2O 1.10

EtOH 9.87 8:1 EtOH:H2O 10.20 1:1 DMF:MeOH >100

H2O 0.00 2:1 EtOH:H2O 3.33 2:1 DMAc:H2O 9.06

Toluene 3.87 95:5 IPA:H2O 9.45 1:1 DMAc:H2O 0.91

THF >100 90:10 IPA:H2O 10.27 2:1 NMP:H2O 16.93

Heptane 0.00 80:20 IPA:H2O 9.01 1:1 NMP:H2O 1.38

IPAc 22.46 50:50 IPA:H2O 0.12 1:1 Toluene:MeOH 52.46

DMF >100 25:75 IPA:H2O 0.15 1:1 Toluene:MeCN 73.57

NMP >100 2:1 IPA:H2O 4.75 1:1 Toluene:EtOH 31.25

MeOH 17.95 8:1 IPA:H2O 10.61 1:1 Toluene:IPA 22.83

2-methylTHF 60.72 95:5 THF:H2O >100 1:1 IPAc:MeOH 37.36

DCM 49.77 90:10 THF:H2O >100 1:1 MeCN:EtOH 54.20

DMAc >100 80:20 THF:H2O >100 1:1 2-methylTHF:Heptane 1.40

DMSO >100 50:50 THF:H2O 0.69 1:1 THF:MTBE 32.77

EtOAc 49.83 25:75 THF:H2O 0.09 1:1 Toluene:MTBE 5.50

IPA 5.90 2:1 THF:H2O 36.07 1:1 IPAc:MTBE 13.46

MTBE 3.58 8:1 THF:H2O >100 1:1 IPA:MTBE 7.86

2-butanol 4.59 90:10 Acetone:H2O >100 2:1 Acetone:Water 60.48

MEtOAc 76.10 80:20 Acetone:H2O 0.11 1:1 Acetone:Water 15.85

n-propanol 6.85 50:50 Acetone:H2O 0.07 1:1 EtOH:Heptane 8.32

Hexane 0.00 25:75 Acetone:H2O 0.07 1:1 THF:Heptane 2.85

90:10 MeCN:H2O 68.43 2:1 Acetone:H2O 0.08 2:1 THF:Heptane 0.30

80:20 MeCN:H2O 45.79 8:1 Acetone:H2O 49.13 9:1 THF:Heptane 81.30

50:50 MeCN:H2O 0.84 95:5 MeOH:H2O 10.17 1:1 IPA:Heptane 3.63

25:75 MeCN:H2O 0.08 90:10 MeOH:H2O 8.75 1:1 Toluene:Heptane 0.37

95:5 EtOH:H2O 11.79 50:50 MeOH:H2O 0.17 2:1 IPAc:Heptane 7.81

90:10 EtOH:H2O 11.59 2:1 MeOH:H2O 0.98 1:1 IPAc:Heptane 3.01

80:20 EtOH:H2O 7.50 8:1 MeOH:H2O 8.74 1:1 MTBE:Heptane 0.22

1:1 DCM:Heptane 0.00

• High-throughput solubility data provides a first set of potential solvent systems:

➢ Good solvents

➢ Good antisolvents

➢ Risky systems

API with two known forms

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• Both, polar and apolar solvent systems successfully generated the desired Form 2 at lab scale

• Seeded process with supersaturation control expected to yield desired form

Form 2

Form 1

EtOAc/Heptane

MeCN/Water

First results at 300 mg scale

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• Particle morphoplogy changes in different solvents– potential for different impurity rejection?

Apolar solvent systems Polar solvent system

EtOAc/Heptane IPAc/Heptane MeCN/Water

Crystallization and impurities in the literature

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Dichloromethane Ethanol

Development work for 2nd GMP delivery

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Apolar solvent systems Polar solvent system

EtOAc/Heptane 2-MeTHF/Heptane MeCN/Water

EtOAc/Heptane 2MeTHF/Heptane MeCN/Water

API purity 99.9% LCAP 99.9% LCAP

Data-rich experiment at 3 g scale – EtOAc/Heptane

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Yield ≈ 96 %

Vol. prod. ≈ 62 g/L

Cycle time ≈ 18 h

Form impurity (rods)Temperature

Crust formation

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Hot reactor walls induce “creeping”:

Cool reactor walls avoid “creeping”, but still on probes & stirrer:

Activated carbon treatment & rex in 2MeTHF/Heptane

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Pure APICrude API

Crystallization +

Activated carbon

Successful 2nd GMP delivery (27 kg API)

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• Improved chemistry reduced RM cost by 40x

• New API crystallization process

• Eliminates the need for recrystallization due to improved impurity rejection

• Ensures robust API form control (lower seed mass was compensated by extended seed age)

• Rejects color using AC

• Delivered 27 kg API with a higher crystallization yield of +13%

Quantiles [µm]

x10 1.4

x50 4.1

x90 8.1

Jet-milled API

Potential to eliminate jet milling?

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• Unseeded high-shear reverse additions have been performed in MeCN/Water and EtOAc/Heptane API crystallization process

• Polar and apolar systems yielded mix of forms

• Ongoing work with seeded reverse addition

Summary

18Thank you!

• Different particle morphologies can indicate impurity rejection differences (lower aspect ratio correlates with higher purity)

• Combination of miniaturization and data-rich experiments allowed for an optimized process design regarding impurity rejection, form control, de-coloring, and process yield

• Further work on bottom-up process with form control ongoing

Acknowledgements- Erica Schwalm- Eric Ashley- Eric Sirota- Siwei Zhang- Yonggang Chen

Q&A