1 polymorphism and pharmaceuticals steve byrn [email protected]
TRANSCRIPT
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DimensionsDimensions
• Solid State Chemical Science
• Regulatory
• Patents
• Speed to market Public health Costs
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Solid State TechnologySolid State Technology
Dosage Choice Manufacturing
Formulation & Drug Delivery
Marketing & Further Product ImprovementsPatents
Quality Control
RegulatoryStability
Research
Purification and Process
Development
Toxicology
no
d
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Cardinal RulesCardinal Rules
HISTORICAL DATA DERIVED FROMTRIAL-N-ERROR EXPERIMENTATION
HEURISTIC RULES“Rules of Thumb”
EMPIRICAL
MODELS
MECHANISTICMODELS
Rules
Make the SameThing Every Time
Know What You Have
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Eliminate The Pipeline ProblemEliminate The Pipeline Problem
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Process Development
Clinical Trials
Drug ProductManufacture
Drug SubstanceManufacture
Formulation
Process Development
Preformulation
Synthesis
DISCOVERY LAUNCH1 - 6 Years
Polymorph DiscoveryPolymorph Discovery
Early full Comprehensive(lifecycle)
may include salt, cocrystal, &
amorphous forms
Focused
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Frequency of Multiple FormsFrequency of Multiple Forms
Based on about 150 studies:
87% > than 1 form51% multiple polymorphs 37% hydrates39% amorphous 31% solvates
SSCI Data
0
5
10
15
20
25
30
35
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Num
ber o
f Com
poun
ds
Number of Solid Forms
(Pat Stahly)
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Prediction from Energy-Temperature Prediction from Energy-Temperature DiagramsDiagrams
E nergy-Tem perature D iagram
SolubilityStability
Dissolution Dosage Form
0
10
20
30
40
50
60
70
0 10 20 30 40 50 60 70 80 90 100 110 120
Time (min)
Flu
oxet
ine
HC
l Con
cent
ratio
n (m
M)
Fluoxetine HCl:Fumaric Acid
Fluoxetine HCl:Succinic Acid
Fluoxetine HCl
Fluoxetine HCl:Benzoic Acid
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ICH Decision Tree - Polymorphs: ICH Decision Tree - Polymorphs: Question 1Question 1
Note broad definition of polymorphs
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ICH Decision Tree - Polymorph Question 2ICH Decision Tree - Polymorph Question 2
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ICH Decision ICH Decision Tree - Question 3Tree - Question 3
For solid dosage form or liquid containing undissolved drug substanceN.B. Undertake the following process only if technically possible
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Law,et al., J. Pharm. Sci. 93 (2004) 563
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Law,et al., J.Pharm.Sci. 93 (2004) 563
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15(Ralph Pfeiffer)
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FFoouurr
SSii
mmppllee
RROOYY
DDeerriivvaattiivveess
S
NC
NH
NO2
4'
5Me
S
NC
NH
Me
NO2
4'
5Me
S
NC
NH
NO2
4'
5
S
NC
NH
Me
NO2
4'
5
C. A. Bunnell (Eli Lilly, 1995) X. He, U. Griesser (2001)
H. Li (2003) J. Hatakama (2005)
The Original ROY 4’-Me-ROY
5-norMe-ROY 4’-Me-5-norMe-ROY
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TThhee
OOrriiggiinnaall
RROOYY
S
NC
NH
NO2
4'
5Me
ROYC.A. Bunnell (Eli Lilly, 1995)
OPorange plates
ORPorange-red plates
Rred prisms
ONorange needles
YNyellow needles
Yyellow prisms
Yu, et. al. J. Am. Chem. Soc. 2000, 122, 585-591
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44’’--MMee--RROOYY
• Four Polymorphs
S
NC
NH
Me
NO2
4'
5Me
DRdark red
LRlight red
Rred
Oorange
He, et. al. J. Pharm. Sci. 2001, 90, 371-388.
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55--nnoorrMMee--RROOYY
• Two Polymorphs
S
NC
NH
NO2
4'
5
100 m
Oorange
100 m
Rred
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FFoouurr
SSii
mmppllee
RROOYY
DDeerriivvaattiivveess
S
NC
NH
NO2
4'
5Me
S
NC
NH
Me
NO2
4'
5Me
S
NC
NH
NO2
4'
5
S
NC
NH
Me
NO2
4'
5
C. A. Bunnell (Eli Lilly, 1995) X. He, U. Griesser (2001)
H. Li (2003)
6 Polymorphs 4 Polymorphs
2 PolymorphsThis Work
? Polymorphs
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SSyynntthheessiiss
ooff
44’’--MMee--55--nnoorrMMee--RROOYY
98.4g (53%) 46.8g (18%)
ca 36g (14%)a
a: Needs further purification
F
NO2
NaH / THFS
NC
NH
NO2
S
NC
H2NS
S OH
HO
CN
CN
( 2 eq)
NaOH
1 2
3
4
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PPoollyymmoorrpphh
DDiissccoovveerryy
• 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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• Initial crystallization studies gave only a red form (R4’M5N).
• Is this the first ROY derivative with only one form?
RReedd
FFoorrmm
RR44’’
MM55NN
-1000
0
1000
2000
3000
4000
5000
6000
5 10 15 20 25 30 35 40
2 Theta
Toluene
CH3CNEtOH
IPA
R4’M5N
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SSeeeeddiinngg
wwiitthh
ootthheerr
RROOYY
DDeerriivvaattiivveess
• Using yellow needles of 5-Et-ROY as seed crystals
• Slow evaporation method in EtOH at room temperature afforded orange form (O4’M5N).
Not cocrystal
Pure orange form
S
NC
NH
NO2
5
Y5ETS
NC
NH
Me
NO2
4'
5
O4’M5N
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XXRRPPDD
OO44’’
MM55NN aanndd
RR44’’
MM55NN
-1000
0
1000
2000
3000
4000
5000
6000
7000
5 10 15 20 25 30 35 40
2 Theta
Jin-03047A
Jin-03041B
R4’M5N
O4’M5N
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NNeeww
FFoorrmm
ooff
44’’--MMee--55--nnoorrMMee--RROOYY
OO44’’
MM55NN
R4’M5N O4’M5N Y5ET
Color
Red Orange Yellow
XRPD A B -
mp (°C)(Capillary)
142-143 139-140 104-105
R4’M5N has higher mp.
R4’M5N is stable form ?
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XX--RRaayy
CCrryyssttaallllooggrraapphhyy
• Crystal structures of each form were solved.
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TThhee UUnniitt CCeellllss
O4’M5N R4’M5N
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EEqquuiilliibbrriiuumm SSoolluubbiilliittyy iinn EEttOOHH
RReessuullttss
• van’t Hoff Plot
y = -4788.7x + 16.684
R2 = 0.9955
y = -4222.8x + 15.002
R2 = 0.9939
-0.4
0.0
0.4
0.8
1.2
1.6
2.0
2.4
2.8
3.2
0.0028 0.0030 0.0032 0.0034 0.0036
1/T
Ln
C
ln C = a + b•T-1
r2 > 0.99
a b r2
R4’M5N
15.002
-4222.
80.994
O4’M5N
16.684
-4788.
70.996
Regression Coefficients
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EEqquuiilliibbrriiuumm SSoolluubbiilliittyy iinn EEttOOHH
RReessuullttss
• Relative Energy-Temperature Diagram
Free Energy-Difference
ΔGR,O
= RTln(CR /C
O)
y = -13.985x + 887.26
-200
0
200
400
600
800
1000
0 10 20 30 40 50 60 70
Temperature [C]
Fre
e E
nerg
y D
iffer
ence
[J/m
ol]
63.5°C
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.
a b
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RReellaattiivvee
EEnneerrggyy--TTeemmppeerraattuurree
DDiiaaggrraamm
Dc
a
l
c
(calcd. density)mp
Solubility
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CCoonncclluussiioonn
• 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 FormsStrategies to Find New Forms
• 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)
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Why Capillaries?Why Capillaries?
supersaturation ratiosas high as 60 have beenachieved
(Ken Morris)
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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 ROYFundamental Studies Using ROY
Morris, K.; Hilden, J.; Kelm, M.; Reyes, C. Purdue University, to be published
0
2
4
6
8
10
12
2 4 6 8 10 12 14 16
Saturation at Crystallization
Fre
quen
cy ONYPORPNew?
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OH3C
CH3
OThe anti-inflammatory Relafen®One solid form reported in the literature
SSCI Case Study: NabumetoneSSCI Case Study: Nabumetone
• 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)
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1000 m
Nabumetone Form II
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X-ray Powder Diffraction X-ray Powder Diffraction Software and Analysis of Software and Analysis of Crystal Structures using Crystal Structures using
XRPDXRPD
Co
nfi
de
nti
al
(Simon Bates)
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Figure 1Example 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
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XRPD Pattern Analysis - Use of Electron XRPD Pattern Analysis - Use of Electron Density map for RietveldDensity map for Rietveld
Rietveld analysis (MAUD) using electron density for Quantitative analysis
Form A: 67.4%
Form C1: 32.6%
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XRPD Pattern Analysis: IndexingXRPD 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 XRD Pattern Analysis: Physical Properties PredictionPrediction
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!
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XRPD Pattern Analysis: The Next Step - 2.) XRPD Pattern Analysis: The Next Step - 2.) Pair-Wise Distribution FunctionsPair-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
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XRPD Pattern Analysis - PDF & Order - XRPD Pattern Analysis - PDF & Order - Disorder relationshipsDisorder relationships
Measured XRPD patterns - are materials related?
Significant Peak broadening!
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XRPD Pattern Analysis - PDF & Order - XRPD Pattern Analysis - PDF & Order - Disorder relationshipsDisorder relationships
Loss of long range order in disordered form
Local Order matches
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5.33Å
10.3Å17.1Å
Characteristic Length Scales
Distance in Å
XRPD Pattern Analysis - The PDF Transform XRPD Pattern Analysis - The PDF Transform for Indomethacin (Gamma)for Indomethacin (Gamma)
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10.3Å Cl-Cl distances
17.1Å Cl-Cl distancesView of crystal structure for Gamma form using Cl as a central atom.
Cl forms a very simple lattice acting as a frame for the organic components.
Gamma Form
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12 minutes
30 minutes
0 minutes
XRPD Pattern Analysis - The PDF TransformXRPD Pattern Analysis - The PDF Transform
Cryo-grinding of IMC gamma
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52Distance in Å
Loss of long range order
12 minutes
30 minutes
0 minutes
40.0Å
XRPD Pattern Analysis - The PDF TransformXRPD Pattern Analysis - The PDF Transform
Residual memory
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Utilization of XRPD SoftwareUtilization 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
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FDA InitiativesFDA Initiatives
Critical Path
Industrialization - GMP 21st Century Safety Medical Utility
PATQUALITYSYSTEMS
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FDA Critical PathFDA Critical Path
Safety
Medical
Industrial-ization
Critical Path
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PAT = Process UnderstandingPAT = Process Understanding
HISTORICAL DATA DERIVED FROMTRIAL-N-ERROR EXPERIMENTATION
HEURISTIC RULES“Rules of Thumb”
EMPIRICAL MODELS
MECHANISTICMODELS
Rules
Current Level of Knowledge
Desired Level of Knowledge
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PAT Integrated into Drug Substance PAT Integrated into Drug Substance ManufacturingManufacturing
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Sensor StrategySensor Strategy
PCCP variables –Model dev/refine
What variables should be important?
Sensor development and refinement
What variables are measurable?
Production - Scale up/down/same
Product performance
PCCP variables –Model dev/refine
What variables should be important?
Sensor development and refinement
What variables are measurable?
Production - Scale up/down/same
Product performance
(Ken Morris)
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Raman Monitoring of Polymorph During Raman Monitoring of Polymorph During CrystallizationCrystallization
0 100 200 300 1200 1300 1400 1500
0
50
100
150
200
250
Co
nce
ntr
atio
n (
mg
/mL
)
Time (minutes)
Solute FormIII FormI
(Lynne Taylor)
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Desired Future StateDesired 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
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ConclusionConclusion
• 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
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Eliminate The Pipeline ProblemEliminate The Pipeline Problem
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XXRRPPDD
PPaatttteerrnnss
• Comparison between theoretical and observed pattern
O4’M5N R4’M5N
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Number of ExperimentsNumber of Experiments
• 60 solvents – 60x60=3600
• 10 concentrations – 36000
• 10 temperature changes (or 10 evaporation rates) – 360,000
• With and without stirring – 720,000