2
DimensionsDimensions
• Solid State Chemical Science
• Regulatory
• Patents
• Speed to market Public health Costs
3
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
4
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
5
Eliminate The Pipeline ProblemEliminate The Pipeline Problem
6
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
7
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)
8
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
9
ICH Decision Tree - Polymorphs: ICH Decision Tree - Polymorphs: Question 1Question 1
Note broad definition of polymorphs
10
ICH Decision Tree - Polymorph Question 2ICH Decision Tree - Polymorph Question 2
11
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
12
13
Law,et al., J. Pharm. Sci. 93 (2004) 563
14
Law,et al., J.Pharm.Sci. 93 (2004) 563
15(Ralph Pfeiffer)
16
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
17
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
18
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.
19
55--nnoorrMMee--RROOYY
• Two Polymorphs
S
NC
NH
NO2
4'
5
100 m
Oorange
100 m
Rred
20
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
21
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
22
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
23
• 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
24
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
25
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
26
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 ?
27
XX--RRaayy
CCrryyssttaallllooggrraapphhyy
• Crystal structures of each form were solved.
28
TThhee UUnniitt CCeellllss
O4’M5N R4’M5N
29
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
30
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
31
RReellaattiivvee
EEnneerrggyy--TTeemmppeerraattuurree
DDiiaaggrraamm
Dc
a
l
c
(calcd. density)mp
Solubility
32
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.
33
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)
34
Why Capillaries?Why Capillaries?
supersaturation ratiosas high as 60 have beenachieved
(Ken Morris)
35
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)
36
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?
37
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)
38
1000 m
Nabumetone Form II
39
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)
40
Figure 1Example dendrogram from pattern matching program
based on modified HCA
41
Figure 2
Pattern matching result
42
Figure 3
Single cluster
43
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%
44
XRPD Pattern Analysis: IndexingXRPD Pattern Analysis: Indexing
Monoclinic P21/n: a=14.724 b=7.0953 c=21.5057 beta=103.77
45
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!
46
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
47
XRPD Pattern Analysis - PDF & Order - XRPD Pattern Analysis - PDF & Order - Disorder relationshipsDisorder relationships
Measured XRPD patterns - are materials related?
Significant Peak broadening!
48
XRPD Pattern Analysis - PDF & Order - XRPD Pattern Analysis - PDF & Order - Disorder relationshipsDisorder relationships
Loss of long range order in disordered form
Local Order matches
49
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)
50
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
51
12 minutes
30 minutes
0 minutes
XRPD Pattern Analysis - The PDF TransformXRPD Pattern Analysis - The PDF Transform
Cryo-grinding of IMC gamma
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
53
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
54
FDA InitiativesFDA Initiatives
Critical Path
Industrialization - GMP 21st Century Safety Medical Utility
PATQUALITYSYSTEMS
55
FDA Critical PathFDA Critical Path
Safety
Medical
Industrial-ization
Critical Path
56
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
57
PAT Integrated into Drug Substance PAT Integrated into Drug Substance ManufacturingManufacturing
58
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)
59
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)
60
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
61
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
62
Eliminate The Pipeline ProblemEliminate The Pipeline Problem
63
XXRRPPDD
PPaatttteerrnnss
• Comparison between theoretical and observed pattern
O4’M5N R4’M5N
64
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