Embed Size (px)
Citation preview
Accelerating Drug Development through Automation
Crystallization WorkshopMilan, 7th June 2018
Dr Edwin AretPrincipal Scientist Solid State Chemistry
Outline
• Alcami• Solid State Chemistry• Drug Development
• Process• Form Selection
• Case Studies
2
Welcome to Alcami
3
Launched 2016
Alcami is a world-class contract development and manufacturing organization (CDMO) headquartered in Durham, North Carolina. Alcami provides solutions tailored to small and mid-size pharmaceutical and biotechnology companies. With over 1,000 employees operating at seven sites in the United States and Europe, our combined capabilities include:
• API development and manufacturing• Solid state chemistry• Formulation development• Analytical development and testing services• Clinical and commercial finished dosage form manufacturing (oral solid dose and parenteral)• Packaging and stability services
Alcami offers an end-to-end outsourcing opportunity that can be integrated for a less fragmented and faster pathway for products through the clinic toward commercialization, as well as individualized development and manufacturing services.
Facilities Overview
4
Our Approach
5
Science & Technology Proven technical expertise for optimal right first time process
Speed through clinic and launch
Technical platforms to address unforeseen molecule constraints & minimize clinical delays
TrustRegulatory and Safety Expertise
Industry Leader in Innovation and Regulatory Changes
Multi-Facility Offerings for De-Risked Program and Scale Up Support
Easy-to-Work-WithSingle Program Manager Supported by Project Managers, Quality and Operations
Single Master Service Agreement Across All Service Offerings
Diversity>100 Early Stage Products in Portfolio
>50 Late Stage Products in Portfolio
>40 Commercial Products in Portfolio
Excellence in Stand Alone Program or Integrated End-to-End Offering
IntegrityService Offering Solutions Through Clinic to Launch
Dedicated to Navigating Companies To Success
Invest Back Into Sites- >$20M Annually
Industry Leading Full Service CDMO
>$200M Revenue/Annually
1000 Employees
7 Sites Globally
Solid State Chemistry
Analytical Services
6
Process Chemistry
• Crystallization Study – isolate and purify stable solids
• PhysChem Characterization – material identification, stability
• Solubility Determination – in production solvents and buffer solutions
• Salt Selection – suitable form selection, improve solubility
• Polymorph Study – find a form for further development, IP screens
• Process Development – range finding DoE, metastable zone width
• Particle Habit Engineering – control of particle size and shape
• Pre-formulation – dissolution rate, excipient compatibility
A Center of Excellence for Crystallization and Solid State Chemistry
Solid State Chemistry
Study of the PhysicoChemical and Mechanical Properties• Development Strategy• Risk Assessment • Target Product Profile
Development by combination of DoE, PCA and HTS • Route Scouting• Range Finding• Scale-up Optimization
7
Design of Experiments (DoE)
DoE provides an overview of the interaction of factors, without the need of testing all possible conditions
• Continuous factors• Temperature, concentration, addition rate, stoichiometry…• Choose any level / range
• Discrete factors• Reagent, catalyst, ligand, solvent…• Selection constrained by availability / existence
8
Principle Component Analysis (PCA)
• PCA allows conversion of discreet chemicals into continuous variables• e.g. solvents: polarity, polarizability, H-bonding
9
PC2
PC1
Combining DoE and PCA
• identify factors and set ranges• define solvent space• select responses• select HTS protocol• choose design
• model data• validate predictions
10
Drug Development
11
Process Development
12
2 ml 50ml
1 L450 L
QC/QAReleaseDemo Batch
Typical Deliverables:-Proof of Concept-Use Test of Raw Mat.-Confirm Specs-Material for Ref. Standard
MedChemRoute Scouting
Process-Process R&D-Analytical R&D-Solid State R&D
GMP Scale Up
Analytical Val.
Typical Deliverables:-GMP Batch-Validated Methods-Qualified Reference-Validation Protocols-Validation Reports
Typical Deliverables:-CoA-TSE Statement-GMP Compliance-IMPD/IND Support
Typical Deliverables:-Fit Process-Fit Analytical Methods-Target Specs-Material for Analytical Val.
Process Development
UnchainedLabs Automation
• dSPR (deck Screening Pressure Reactor)• Parallel screening 48 * 1 ml• Pressure ~5 bar / protected atmosphere• Controlled heating / cooling 10-150C, stirring• e.g. Hydrogenation, cat-screens
14
Technobis Crystal 16
• Process Chemistry• Parallel 16 * 1 ml• Stirring, heating-cooling -20 – 200C, turbidity• Selection process conditions• Metastable zone width• Seeding conditions, crystallization behavior
15
Conc
entr
atio
n
Temperature
nucleation curve is variable,determined by crystallization conditions
solubility curve is fixed
Cooling
MSZW data
Meta-stable Zone Width: determine the solubility in process solvent(s) at several temperatures.
Technobis Crystalline
• Process Chemistry• Parallel 8 * 5 ml• Stirring, heating-cooling -20 – 200C, turbidity, camera, particle size and shape• Selection process conditions• Metastable zone width• Seeding conditions, crystallization behavior
17
Crystalline PSD data
• Nucleation / crystal growth:
18
Crystal Habit
• Select crystallization conditions to avoid fines, platelets or needles • Control for good filtration behavior and consistent dissolution rate• Avoid solvent inclusion, amorphous content, agglomerates
improvedfiltration
improveddissolution
19
Process chemistry
• Parallel reactor systems• 1 Project Database; combined process conditions and (in-situ) analytics• MiniTab17 DoE software• Optimization, reproducibility, scalability
UnchainedLabsScreening Platform
Technobis Crystal16 / Crystalline16 x 2 ml / 8 x 8 ml
MT-MultiMax/ LabMax4 x 50 ml / 2 x 250 ml / 1-2 L
Temperature, pH, dosing, seeding
FBRM, turbidity, video, PSD
Filtration rate, drying time
Database
20ELN
UnchainedLabs Automation
• Solid Dispenser• Dosing solids in well-plates or glass vials• 1 mg – 1 g
21
Parallel Screening
• Obtain an overview of the crystallization behavior• Produce one suitable form for the stage of development• Find and characterize as many forms as time/costs allows• Compare critical properties like solubility, stability, bioavailability
• Heating – cooling• Stirring / slurry• Hot-filtration• Anti-solvent addition• LC dilution• Crystallization
22
Protocol Form Selection
23
High-Throughput Analytics
• Analytics:• Solids / solution prepared on deck• Avoid manual repetitive handling• Software integrated
• Use equipment measurement software• Data stored in one project folder
• (u)HPLC
• XRPD + imaging
24
Bruker D8 Discover High-Resolution High-Throughput XRPD
• four 96 well-plates auto-sampler• xyz-screening stage • specially designed optics • images before and after• crystallization plate = XRPD
sample holder• raw data analysis by Polysnap
and TOPAS• reduce 2 FTE weeks into 1 day
25
Form Selection
• High-throughput crystallization platform (400 exp./day)• Project Database; library, dosing, experimental conditions and analytics
UnchainedLabsProtégéSolid Dispense System
UnchainedLabsCM2Crystallization Platform
Technobis Crystal16 / Crystalline
Bruker D8 Discover HR-HTS XRPD
HPLC / UPLC
FT-IR, DSC, TGA, Microscopy…
Database
Report / raw data
26
Case Studies
27
Suzuki cross coupling
28
R1 X + B
OR
OR
R2R1 R2 + B
OR
OR
RO[Pd]
• C-C bond formation• Palladium catalyzed cross coupling reaction
Organic halide Organo boron
Suzuki cross coupling
# Type 1 2 3 4 5 6 7 8
ABase Dipea K2CO3 CsCO3 Et3N Dipea K2CO3 CsCO3 Et3N
Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO
BBase Dipea K2CO3 CsCO3 Et3N Dipea K2CO3 CsCO3 Et3N
Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO
CBase Dipea K2CO3 CsCO3 Et3N Dipea K2CO3 CsCO3 Et3N
Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO
DBase Dipea K2CO3 CsCO3 Et3N Dipea K2CO3 CsCO3 Et3N
Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO
EBase Dipea K2CO3 CsCO3 Et3N Dipea K2CO3 CsCO3 Et3N
Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO
FBase Dipea K2CO3 CsCO3 Et3N Dipea K2CO3 CsCO3 Et3N
Solvent MeOH MeOH MeOH MeOH DMSO DMSO DMSO DMSO
29
Variables: solvent (4), base (4), temperature (2), time (2)Responses: conversion, reproducibility
Suzuki cross coupling
01020304050607080
90
100
Conv
ersio
n[%
] / σ σ DMSO
σ IPAσ Ethanolσ MethanolDMSOIPAEthanolMethanol
65°C90°C
65°C16 hours24 hours 90°C
30
Methanol, inorganic base, 90°C, 24h -> best reaction condition for scaling up
MSZW data
• ACN is used as process solvent, poor nucleation control• Other solvent? Anti-solvent?
31
MSZW data
Cooling Crystallization Seeding
Crystalline: Compound oils out, solidifies and clusters of needles grow from it. Seeding gives block-shaped crystals.
• Other solvents: not soluble or solvates• Anti-solvent: oiling out• Seeding?
Filtration issues
• Material showed filtration issues• Isolated using DMSO or DMSO/water• Small particles; fines < 20µm
• Recrystallization experiments new polymorph• Isolated using DMSO/methanol, good filtration
• Advantages new form• Improved filtration• Thermodynamically more stable • Less hygroscopic
33
Filtration issues
Reaction mixture DMSO Reaction mixture DMSO/MeOH (1/1)
34
Case Study - solvent
• Solubility determination for recrystallization
35
Solvent PCA Solubility (mg/ml) USP classification
2-ethyl-1-butanol 0 0 0 < 0.1 Practically insoluble2-butanol -1 -1 -1 0.1-1 Very slightly solubleMethanol -1 -1 1 1-11 Slightly solubleWater -1 -1 1 < 0.1 Practically insolubleDimethylsulfoxide -1 1 -1 0.8-11 Slightly solubleethyl salicylate -1 1 1 < 0.1 Practically insolubleethyl acetate 1 -1 -1 0.1-1 Very slightly solublen-heptane 1 -1 1 < 0.1 Practically insolubleAnisole 1 1 -1 0.1-1 Very slightly solubleCyclohexane 1 1 1 < 0.1 Practically insoluble
1
2
3
4
56
7
89
10
11
12
13
14
15
1617 18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3334
35
36
37
38
3940
4142
43
44
45
46
47
48
4950
51
52
53
54
55
56
5758
59
60
61626364
65
66
67
68
69
70 71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
9192
93
94
95
96
97
9899
100 101
102
103
104
105106
107
108
109
110111
112
113
114
115
116
117
118
119
120
121122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
-6
-4
-2
0
2
4
6
-12 -10 -8 -6 -4 -2 0 2 4 6 8 10
Pola
rity
(PC2
)
Polarisability (PC1)
Case Study - solvent
• Solubility determination for recrystallization• Preferably no high boiling solvents• High yield, high purity• Polymorph Form A
36
Solvent PCA XRPDMethanol -1 -1 1 Form AEthanol -1 -1 0 Form A2-Propanol -1 -1 -1 Form A2-Butanol -1 -1 -1 Form AEthyl acetate 1 -1 -1 Form A + add. peakEthyl formate 0 -1 -1 Form A + add. peakTetrahydrofuran 1 -1 -1 Form AAcetone -1 -1 -1 Form BFormic acid -1 -1 1 No solidsAcetic acid -1 -1 1 No solids
-6
-4
-2
0
2
4
6
-10 -8 -6 -4 -2 0 2 4 6 8
PC2
PC1
Acid
Alcohol
Alkylamide
Amide
Aromatic
Aryl Halide
CHC
Ester
HC
Ketone
Nitrile
Nitro
Sulfoxide
Water
Case Study - solvent
• Solubility determination for recrystallization
• 10 solvents provide the overview of the whole solvent space• Selection of suitable / alternative process solvents based on PCA• Expected solubility behavior based on PCA confirmed
• No guarantee on polymorphic form• Form selection screening still required
37
Summary
• Drug development is troubleshooting and risk management.
• Streamline the R&D, integrate process development, analytics and solid state chemistry to shorten timelines and strengthen the added value.
• Have the data accessible and searchable for the project team, not only a report with the conclusions.
• Use of automation leads to smart experiments for the overview to select optimal conditions. Screen more different factors, not just do more experiments.
38
Stay connected at alcaminow.com
Thank you!
