Transcript No Slide Title

Polymorphism and
Pharmaceuticals
Steve Byrn
[email protected]
1
Dimensions
•
•
•
•
Solid State Chemical Science
Regulatory
Patents
Speed to market


Public health
Costs
2
Solid State Technology
3
Cardinal Rules
Know What
You Have
Rules
Make the Same
Thing Every Time
MECHANISTIC
MODELS
EMPIRICAL
MODELS
HEURISTIC RULES
“Rules of Thumb”
HISTORICAL DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
4
Eliminate The Pipeline Problem
5
Polymorph Discovery
Synthesis
Drug Substance
Manufacture
Process Development
Preformulation
Formulation
Drug Product
Manufacture
Process Development
Clinical Trials
1 - 6 Years
DISCOVERY
Early
full
Focused
may include salt,
cocrystal, &
amorphous forms
LAUNCH
Comprehensive
(lifecycle)
6
Frequency of Multiple Forms
35
Based on about 150
studies:
Number of Compounds
87% > than 1 form
51% multiple polymorphs
37% hydrates
39% amorphous
31% solvates
30
25
20
15
10
5
0
1
SSCI Data
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17
Number of Solid Forms
(Pat Stahly)
7
Prediction from Energy-Temperature
Diagrams
Solubility
Stability
Energy-Temperature Diagram
Dissolution
Dosage Form
70
Fluoxetine HCl Concentration (mM)
Fluoxetine HCl:Fumaric Acid
60
Fluoxetine HCl:Succinic Acid
Fluoxetine HCl
Fluoxetine HCl:Benzoic Acid
50
40
30
20
10
0
0
10
20
30
40
50
60
70
80
90
100
110
120
Time (min)
8
ICH Decision Tree - Polymorphs:
Question 1
Note broad definition of polymorphs
9
ICH Decision Tree - Polymorph Question 2
10
ICH Decision
Tree - Question 3
For solid dosage form
or liquid containing
undissolved drug
substance
N.B. Undertake the
following process only
if technically possible
11
12
Law,et al., J. Pharm. Sci. 93 (2004) 563
13
Law,et al., J.Pharm.Sci. 93 (2004) 563
14
(Ralph Pfeiffer) 15
Four Simple ROY Derivatives
NC
4'
Me
NC
4'
5
N
H
5
Me
S
NO2
S
NO2
4’-Me-ROY
The Original ROY
C. A. Bunnell (Eli Lilly, 1995)
NC
4'
Me
N
H
X. He, U. Griesser (2001)
Me
NC
4'
5
N
H
5
S
NO2
N
H
S
NO2
5-norMe-ROY
4’-Me-5-norMe-ROY
H. Li (2003)
J. Hatakama (2005)
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The Original ROY
ON
orange needles
OP
orange plates
NC
4'
5
N
H
ORP
orange-red plates
S
Me
NO2
YN
yellow needles
ROY
C.A. Bunnell (Eli Lilly, 1995 )
R
red prisms
Y
yellow prisms
Yu, et. al.J. Am.Chem. Soc. 2000, 122, 585-591
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4’-Me-ROY
• Four Polymorphs
R
red
DR
dark red
Me
NC
4'
5
N
H
Me
S
NO2
O
orange
LR
light red
He, et. al.J. Pharm. Sci. 2001, 90, 371-388.
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5-norMe-ROY
• Two Polymorphs
O
orange
NC
4'
100 m
5
N
H
S
NO2
R
red
100 m
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Four Simple ROY Derivatives
NC
4'
Me
NC
4'
5
5
Me
N
H
S
Me
N
H
NO2
S
NO2
C. A. Bunnell (Eli Lilly, 1995)
6 Polymorphs
NC
4'
X. He, U. Griesser (2001)
4 Polymorphs
Me
NC
4'
5
N
H
5
S
NO2
H. Li (2003)
2 Polymorphs
N
H
S
NO2
This Work
? Polymorphs
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Synthesis of 4’-Me-5-norMe-ROY
CN
S
OH
( 2 eq)
NO2
CN
HO
S
1
NC
F
NC
NaOH
H2N
S
2
98.4g (53%)
3
NaH / THF
N
H
NO2
S
4
46.8g (18%)
ca 36g (14%)a
a: Needs further purification
21
Polymorph Discovery
•
•
•
•
•
•
•
•
Simple heat-cool method
Evaporation method
Vapor diffusion method
Hotstage/melt methods
Vapor deposition method
Rapidly changing the
solvent by pouring the
solution into anti-solvent
Even for solvent based
methods there are
> 700,000 experiments
Need rational approach
Vapor diffusion
Vapor depostion
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Red Form
R4’M5N
• Initial crystallization studies gave only a
red form (R4’M5N).
6000
Toluene
CH3CN
EtOH
IPA
5000
4000
3000
2000
R4’M5N
1000
0
-1000
5
10
15
20
25
30
35
40
2 Theta
•
Is this the first ROY derivative with only one
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Seeding with other ROY Derivatives
•
Using yellow needles of 5-Et-ROY as seed crystals
NC
Me
NC
4'
5
N
H
NO2
•
S
Y5ET
5
N
H
NO2
S
O4’M5N
Slow evaporation method in EtOH at room
temperature afforded orange form (O4’M5N).

Not cocrystal

Pure orange form
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XRPD
O4’M5N and R4’M5N
7000
Jin-03047A
Jin-03041B
6000
5000
4000
3000
2000
1000
R4’M5N
0
O4’M5N
-1000
5
10
15
20
25
30
35
40
2 Theta
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New Form of 4’-Me-5-norMe-ROY
O4’M5N
R4’M5N
O4’M5N
Y5ET
Color
Red
Orange
Yellow
XRPD
A
B
-
142-143
139-140
104-105
mp
(°C)
(Capillary)
R4’M5N has higher mp.
R4’M5N is stable form ?
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X-Ray Crystallography
• Crystal structures of each form were
solved.
27
The Unit Cells
O4’M5N
R4’M5N
28
Equilibrium Solubility in EtOH
Results
3.2
• van’t Hoff Plot
2.8
2.4
ln C = a + b•T-1
Ln C
2.0
r2 > 0.99
1.6
y = -4222.8x + 15.002
1.2
R2 = 0.9939
0.8
0.4
y = -4788.7x + 16.684
0.0
R2 = 0.9955
-0.4
0.0028
0.0030
0.0032
0.0034
0.0036
1/T
Regression Coefficients
a
b
r2
R4’M5N 15.002
-4222.8
0.994
O4’M5N 16.684
-4788.7
0.996
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Equilibrium Solubility in EtOH
Results
• Relative Energy-Temperature Diagram
a
b
a. Calculated values from the regression line, y = 16.684 - 4788.7x.
b. Calculated values from the regression line, y = 15.002 - 4222.8 x.
Free Energy-Difference
ΔGR,O = RTln(CR /CO)
Free Energy Difference [J/mol]
1000
800
600
400
y = -13.985x + 887.26
200
0
-200
0
10
20
30
40
50
60
70
63.5°C
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Relative Energy-Temperature
Diagram
• Dcalc (calcd.
density)
mp
•
• Solubility
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Conclusion
•
Fourth derivative of simple ROY has been newly
synthesized.
•
In initial polymorph study, various crystallization
conditions gave only a red form (R4’M5N).
• Seeding with another ROY (Y5ET) afforded new form
(orange form, O4’M5N).
•
Solubility studies showed that the new form (O4’M5N) is
the most stable form at room temperature
•
The red and orange forms are enantiotropic
•
Red form adopts the most planar conformation among
ROY compounds.
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Strategies to Find New Forms
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•
•
•
•
Guillory methods
Seeding with related compounds
Templated crystallization (Epitaxial growth)
Ultrasound, Lasers
Capillary crystallization



Studied 18 top selling drugs
The form on the market is most stable
Found new forms in 13 cases
• Only 4 are solvates
• In 9 of the 13 cases, the new forms could also be made by
other methods
(Barbara Stahly)33
Why Capillaries?
Energy (ΔG)
high supersaturation
low supersaturation
supersaturation ratios
as high as 60 have been
achieved
polymorph 1
polymorph 2
0
Temperature (K)
(Ken Morris)
34
Plots of
Fraction of
Most Stable
Form vs
Supersaturation
for two conditions:
(top) 50 mg/mL; and
(bottom) 100 mg/mL.
As supersaturation
increases fraction of
most stable form
decreases
Childs, Crystal Growth & Design, 4, 441 (2004)
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Fundamental Studies Using ROY
12
Frequency
10
8
ON
YP
ORP
New?
6
4
2
0
2
4
6
8
10
12
14
16
Saturation at Crystallization
Morris, K.; Hilden, J.; Kelm, M.; Reyes, C. Purdue University, to be published
36
SSCI Case Study: Nabumetone
The anti-inflammatory Relafen®
One solid form reported in the literature
H3C
O
CH3
O
• About 250 traditional solvent experiments provided
only the known Form I
• In capillaries new Form II was obtained in 18% of the
experiments
• Appearance of Form II depended on supersaturation
and quiescence, not solvent
Chyall, Crystal Growth & Design, 2, 505 (2002)
37
Nabumetone Form II
1000 m
38
Confidential
X-ray Powder Diffraction
Software and Analysis of
Crystal Structures using
XRPD
(Simon Bates)
39
Figure 1
Example dendrogram from pattern matching program
based on modified HCA
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Figure 2
Pattern matching result
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Figure 3
Single cluster
42
XRPD Pattern Analysis - Use of Electron
Density map for Rietveld
Form A: 67.4%
Form C1: 32.6%
Rietveld analysis (MAUD)
using electron density for
Quantitative analysis
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XRPD Pattern Analysis: Indexing
Monoclinic P21/n:
a=14.724 b=7.0953
c=21.5057 beta=103.77
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XRD Pattern Analysis: Physical Properties
Prediction
Form A
Morphology
Form C1
Morphology
Density Stability Rule
Form A density = 1.19 g/cm^3
Form C1 density = 1.18 g/cm^3
Experimental Occurrence
Form A: 123 ; Form C1: 32
Inter-conversion: < 95° C: Form C1 >> Form A
Inter-conversion: > 95° C: Form A >> Form C1
Form C1 proved difficult to manufacture!
45
XRPD Pattern Analysis: The Next Step - 2.)
Pair-Wise Distribution Functions
• Fourier Sine Transform of Reduced
Structure Factors -> PDF.




Can be used on 1D or 3D diffraction data.
Used to isolate characteristic repeats and
packing of atoms within solid forms.
Identify Order-Disorder relationships.
Break Down Complex Molecular Structures
into Building Blocks.
• Improved Pattern Matching
46
XRPD Pattern Analysis - PDF & Order Disorder relationships
Significant Peak
broadening!
Measured XRPD
patterns - are
materials related?
47
XRPD Pattern Analysis - PDF & Order Disorder relationships
Local Order
matches
Loss of long range
order in disordered
form
48
XRPD Pattern Analysis - The PDF Transform
for Indomethacin (Gamma)
10.3Å
17.1Å
Characteristic
Length Scales
5.33Å
Distance in Å
49
10.3Å Cl-Cl distances
Gamma Form
View of crystal structure for
Gamma form using Cl as a
central atom.
17.1Å Cl-Cl distances
Cl forms a very simple lattice
acting as a frame for the organic
components.
50
XRPD Pattern Analysis - The PDF Transform
Cryo-grinding
of IMC gamma
0 minutes
12 minutes
30 minutes
51
XRPD Pattern Analysis - The PDF Transform
0 minutes
12 minutes
Loss of long range order
Residual
memory
30 minutes
40.0Å
Distance in Å
52
Utilization of XRPD Software
• Predict Stability


Density rule
Tunnel area
• Select candidates for development

Number of forms not as important as the fact
that several forms exist with about the same
energy
• Analyze amorphous forms


Determine residual order
Predict ease of crystallization
53
FDA Initiatives
Critical Path
Industrialization GMP 21st Century
PAT
Safety
Medical Utility
QUALITY
SYSTEMS
54
FDA Critical Path
Critical Path
Safety
Medical
Industrialization
55
PAT = Process Understanding
Rules
MECHANISTIC
MODELS
Desired Level
of Knowledge
EMPIRICAL
MODELS
Current Level
of Knowledge
HEURISTIC RULES
“Rules of Thumb”
HISTORICAL DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
56
PAT Integrated into Drug Substance
Manufacturing
57
Sensor Strategy
PCCP variables –
Model dev/refine
Production - Scale
up/down/same
Product
performance
Sensor development
and refinement
What variables
should be important?
What variables are
measurable?
(Ken Morris)
58
Raman Monitoring of Polymorph During
Crystallization
250
Concentration (mg/mL)
200
150
Solute
FormIII
FormI
100
50
0
0
100
200
300
1200
1300
1400
1500
Time (minutes)
(Lynne Taylor)59
Desired Future State
• Quality by Design

Know what you have – form discovery
• Specifications based on mechanistic
•
understanding
Continuous quality assurance

Make the same thing every time
• Risk based regulatory scrutiny
60
Conclusion
• Know what you have – polymorph
•
•
•
•
discovery
Make the same thing every time –
characterization/analytical aspects
Speed is paramount
Major advances in application of
XRPD
Quality by design – Risk based
regulations
61
Eliminate The Pipeline Problem
62
XRPD Patterns
• Comparison between theoretical and
observed pattern
O4’M5N
R4’M5N
63
Number of Experiments
• 60 solvents – 60x60=3600
• 10 concentrations – 36000
• 10 temperature changes (or 10
•
evaporation rates) – 360,000
With and without stirring – 720,000
64