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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