This webinar presents crystallization approaches to support drug development needs including examples involving polymorphic purity control, purity upgrade, crystal morphology alteration, and stability enhancement.

1. Dr. Jian Wang
Dr. Jian Wang
Webinar Series
Webinar Series
Effective Development of API Crystallization Process
Effective Development of API Crystallization Process
during Drug Development
during Drug Development

2. 2
Crystallization in Drug R&D
Active
Pharmaceutical
Ingredient
API Crystals
Chemical purity
Structure (polymorphic)
PSD, SA, morphology, density, etc.
Stability (chemical and/or physical)
Hygroscopisity, color, caking, etc.
Drug Product
Bioavailability
Efficacy
Safety
Crystallization
Critical Role in Ensuring Drug Product Quality

3. 3
Crystallization in Drug R&D
Challenges in API Crystallization Process Development
Tight drug development timeline
Limited availability of material
Lack of important information: polymorphs,
stability, solubility, etc.
On-going development of API synthesis
(varying impurity profiles of starting material)
etc.
Product
Isolated Solids
Product
Isolated Solids
Poor Impurity Rejection
Batch 1
Batch 2
Batch 3
Batch 4
target
Batch 1
Batch 2
Batch 3
Batch 4
target
PSD Problems:
Broad PSD
Bimodal PSD
Wrong Size
Ba.-to-Ba. Variability
Wrong Solid Form
Needles
Oil/Amorphous
Agglomerates

4. 4
Crystallization Process Development
Satisfy needs for desired product quality attributes, process efficiency and robustness
through scientific understanding, technology applications, and specialized expertise
Your
Your
Process
Process
Product
Quality
Attributes
Process
Efficiency &
Robustness
IP Safe ,
Environmental
Benign
Your
Your
Process
Process
Product
Quality
Attributes
Process
Efficiency &
Robustness
IP Safe ,
Environmental
Benign
Towards Robust API Crystallization Process

5. 5
Crystallization Process Development
1
1
√
√
√
√
OptiMax
FBRM
G400
EasyMax
Ultrasound Probe
PVM
Integrity
10
Crystal 16
ReactIR 40m
Tools for Process Understanding

6. 6
Crystallization Process Development
Purification
Polymorph
Isolation Particle
Attributes
Control
Seed
Preparation
Process
Optimization
Chiral
Separation
Technology
Application
Process
Tech Transfer
YOUR PROCESS
YOUR PROCESS
Satisfy needs for desired product quality attributes, process efficiency and robustness
through deep scientific understanding, technology applications, and specialized expertise

7. 7
Examples
of Effective Crystallization Process Development

8. 8
Upgrade API Purity
Need for Consistent Impurity Rejection
An API from a
synthetic route
without
isolation step
Irreproducible
impurity rejection
by crystallization
~ 65 wt% of desired API
~ 5:1 cis/trans
Na salt
Other impurities

9. 9
Upgrade API Purity
Nucleation vs. Growth Dominated Process
Process Understanding and Design
0
10
20
30
40
50
60
70
80
10 20 30 40 50 60 70 80
Temperature (℃
℃
℃
℃)
So
lu
b
ility
(m
g/m
l) C* w/crude
MSZW under intensive mixing
MSZW under gentle mixing
Observed
delayed
secondary
nucleation
Seed, followed
by aging and
3~5 steps of
cooling
Concentration
(
g/L
)

10. 10
Upgrade API Purity
Nucleation vs. Growth Dominated Process
Purity Upgrade via Crystallization
A% by HPLC cis/trans
Lot #1 89.9 96.4:4.0
Lot #2 93.7 95.0:5.0
Lot #1 96.6 98.1:1.9
Lot #2 96.8 97.6:2.4
Nucleation Dominated
Growth Dominated
Product Purity
Starting
Material
Process Design
Delivered not only detailed procedure, but also understanding and CPPs

11. 11
Control Polymorph Purity
Understanding
Free
Energy
Supersaturated
state
Form IV (most stable)
Form I
Form II
Form III
Activation
Energy
Ostwald Rule
of Stages
Obtain Pure Meta-Stable Form:
• Avoid generation (or nucleation) of more
stable form
Obtain Pure Stable Form:
• Avoid generation (or nucleation) of meta-
stable forms that are kinetically hindered
from conversion
Typical Targets
of Process Development
Process Development Approach:
1) Collect essential data of the crystallization system, to gain understanding
2) Design and control process based on the understanding
Under a given condition

12. 12
Control Polymorph Purity
Isolation of Meta-stable Form of an API
Essential Data and Understanding
0
20
40
60
80
100
120
140
160
180
200
0 5 10 15 20 25 30 35
Temperature ( C )
Solubility
(
g/L
)
Form I
Form II
MSZW of Form II
0
20
40
60
80
100
120
50% 60% 70% 80% 90% 100%
Solvent % (vol% in solv. + anti-solv.)
Solubility
(
g/L
)
Form I, 0 C Form II, 0 C
Form I, 5 C Form II, 5 C
Form I, 10 C Form II, 10 C
in pure solvent
Decomposition
Greater solubility (or energy difference) between two forms in pure solvent
Form II MSZW near Form I solubility, challenging for Form I isolation
Accelerated decomposition in pure solvent with increasing temperature

13. 13
Control Polymorph Purity
Process Design and Control
Deliver procedure + understanding + CPPs
Isolation of Meta-stable Form of an API
0
20
40
60
80
100
120
140
160
180
200
0 5 10 15 20 25 30 35
Temperature ( C )
Solubility
(
g/L
)
Form I
Form II
MSZW of Form II
Design
Space
Pure Form I
Pure Form I
in high
in high
yield & purity
yield & purity
1. Cool to reach supersaturation
2. Seed w/ Form I
3. Cool to minimize decomposition
4. Add anti-solvent

14. 14
Alter API Morphology
From Acicular to Non-acicular API Product
Loose bulk density
~ 0.1 g/ml
Loose bulk density
~ 0.3 g/ml
1. Solvent system screening
2. Solubility of lead solvent systems
3. Process design and optimization

15. 15
Alter API Morphology
Process
Demo
Scale
(g/batch)
Product Density
Loose
(g/ml)
Tapped
(g/ml)
Acicular
material
0.09 0.26
2
(run 1)
0.34 0.61
2
(run 2)
0.31 0.59
10 0.28 0.57
50 µ
µ
µ
µm 50 µ
µ
µ
µm
50 µ
µ
µ
µm
50 µ
µ
µ
µm 50 µ
µ
µ
µm
50 µ
µ
µ
µm
mill
mill
mill
From Acicular to Non-acicular API Product
Growth Dominated Crystallization followed by Wet Milling

16. 16
Ensure Product Stability
Product of
nucleation
dominated
process
Developed a Growth Dominated Process
Product Color
Post Accelerated Stability Testing
Product of
growth
dominated
process
No difference
in HPLC purity
from client’s
process
from Crystal Pharmatech’s
process

17. 17
Ensure Product Stability
5 10 15 20 25 30 35
2Theta (deg)
0
2000
4000
6000
8000
10000
Intensity
(counts)
Crystalline by XRPD
Product from growth dominated process
Developed a Growth Dominated Process
Product from nucleation dominated process
Reference sample
A proprietary process designed and
controlled to ensure crystal growth

18. 18
Ensure Product Stability
Need to Avoid Caking of a Low Melting API
50μ
μ
μ
μm
50μ
μ
μ
μm
Photo of
API powder
post 7 days at
25°
°
°
°C/60%RH
PLM of
API sample
No polymorphic change
Not hydroscopic

19. 19
Ensure Product Stability
0
200
400
600
800
1000
1200
1400
1600
1800
-5 0 5 10 15 20 25 30
Temperature ( C )
Concentration
(
g/L
)
Solubility
MSZW byCrystal 16
MSZW at 1000 rpm in EasyMax
Process Understanding, Design and Control
Process Optimization towards Growth Dominance
Design
Space
Fast cooling
Slow cooling
Critical Process Parameters
Seeding point
Seed load & property
Cooling profile
Mixing intensity
Moisture in system

20. 20
Ensure Product Stability
Process Optimization towards Growth Dominance
Photo of
API powder
post 7 days at
25°
°
°
°C/60%RH
PLM of
API sample
50μ
μ
μ
μm 50μ
μ
μ
μm
With Nucleation Without Nucleation

21. 21
SUMMARY
Development of API crystallization process is critical to ensure product
quality attributes, and challenging technically and practically.
Process design and control based on understanding of the crystallization
system is a highly effective approach, for developing robust API
crystallization processes.
Allow reliable tech-transfer, insightful trouble shooting and optimization
Minimize chance to fail at production for delivering
Successful examples taking such approach are shown for robust
purification, polymorphic isolation, particle attribute alteration,
chemical/physical stability assurance.

22. 22
ACKNOWLEDGEMENTS
Peng Zhou,
Peng Zhou, Shu
Shu Yu,
Yu, Zhixiang
Zhixiang Shen
Shen, Zhen Tang,
, Zhen Tang, Qiwen
Qiwen Hou
Hou

23. 23
Thanks!
QUESTIONS ?