Webinar Disappearing Polymorphs Stephenson 7th St Dev Group 6-21-17.pdf

Senior Scientific Advisor
317-362-1191
www.crystalpharmatech.com
Greg_stephenson@crystalpharmatech.com
1
Disappearing, Concomitant, Late Appearing and
Missing Polymorphs
6/21/2017 Stephenson, G.A.File
name/location
Pharma Form Finders, LLC
Independent Consultant,
317-362-1191
www.pharmaformfinders.com
Greg.stephenson@comcast.net
Gregory A. Stephenson

2
name/location
Drug Discovery and Development
Pharmaceutical Research and Manufacturers of America
Early
Toxicology
Crystalline/
Salt
Polymorph
Selection
Safety and Dose established, Efficacy
Synthetic Route Design, Crystallization
Dev., Formulation Dev., Analytical
Method Dev., Stability Testing
Specifications

Solid Form Energy Landscape
Solubility Ratio
• Amorphous versus Crystalline 12 to 1652
• 1. Hancock, Bruno C.; Parks, Michael. What is the true solubility advantage for amorphous pharmaceuticals?
Pharm. Res. 2000, 17(4), 397.
• Salt versus Free form
• Anhydrate versus Hydrate 4.09
• Polymorph versus Polymorph 1.76
• 2. Pudipeddi, M., Serajuddin Trends in Solubility of Polymorphs J. PHARM. SCI. 2005, 94(5) 929-939.
3
name/location

4
Physical Form Impact
Physical Properties of API
• Solubility
• Particle Size, Shape (morphology)
• Water sorption/desorption (hygroscopicity)
• Chemical and Physical Stability
• Drying
• Purification and Yield
• Flow and Filterability
Physical Properties on Drug’s Products Dosage Performance
• Stability—Chemical and Physical
• Handling: flow, blending, granulation, tablet compression
• Dissolution
• Special formulation: Suspension
name/location

Absorption via Peroral Administration:
Dependent on solubility (thermodynamic), dissolution rate (kinetic) and permeability
BCS I if entire dose dissolves in 250ml (pH 1 to pH 8)
GL Amidon et al., Pharm Res Vol 12(3): 413-420, 1995
5
name/location

Salt Form Selection and Characterization of LY333531 Mesylate Monohydrate Gary L. Engel,*a Nagy A.
Farid,b Margaret M. Faul,†*c Lori A. Richardson b and Leonard L. Winneroski Int. J. Pharm
0
500
1000
1500
2000
2500
3000
3500
0 8 16 24 32 40 48 56 64 72 80 88 96
Hours
ng/mL
Plas
ma
LY333531(HCl)
LY333531(Mesylate)
LY338522 (HCl)
LY338522 (Mesylate)
Figure 8. Mean plasma concentrations in male beagle dogs orally administered. The AUC values in
each dog were approximately 2.6 times higher following administration of mesylate salts compared
to HCl.
Physical Form (Different salts)
influences Bioavailability
6
name/location

Physical Form and Chemical Stability
Condition API 7 days
%remaining
API 14 days
%remaining
Light 98.3 96.8
40°C 99.0 99.3
50°C 98.9 97.8
70°C 96.8 96.8
40°C/75% 36.8 44.0
50°C/75% 50.7 46.2
Condition API 7 days
%remaining
API 14 days
%remaining
Light 100.3 100.3
40°C 99.9 100.7
50°C 100.0 100.4
70°C 100.0 99.9
40°C/75% 99.9 99.5
50°C/75% 100.3 98.2
Amorphous Salt Crystalline Free base
7
name/location

Pharm. Res. 12 (1995) 945– 954
8
name/location

9
Unusual Crystallization
Behaviour
name/location
Disappearing Crystalline Form: Ampicillin monohydrate
Example 1.

Disappearing and Late Appearing Polymorphs
10
Disappearing Polymorphs Dunitz, J.D.; Bernstein, Acc.
Chem. Res. 1995, 28, 193-200.
Tales of difficulties in obtaining crystals of a particular known form or in
reproducing results from another laboratory (or even from one’s own!) abound. Indeed,
there are cases where it was difficult to obtain a given polymorphic form even though this
had previously been obtained routinely over long time periods. Several monographs
contain explicit or passing references to these problems, l but much of this lore has gone
undocumented, especially in the last 30 years or so. In this Account we present and
discuss old and new examples.
Letter to the Editor: Woodward, G.D.; McCrone, W.C. J. Unusual
crystallization behaviour J. AppL Cryst. (1975). 8, 342.
compounds behaving respectably for many months or years until nucleation of a
more stable form. After this occurs, the previously obtained crystal form cannot
be made to crystallize often even in laboratories many miles away.
name/location

Disappearing and Late Appearing Polymorphs
11
name/location
This is not a new phenomena
1. individual accounts go way back into the 1800’s
2. If one uses the citation index, I think you will find the
occurrence of its reporting just continues to increase in
number/frequency
3. The systems are discovered and understood empirically
you can use prediction tools all day long, but until you can
actually go into the laboratory and get the right molecular
associations of proper configuration and number of molecules,
that is successfully generate a nuclei on a given form, you have
not ―put into practice‖ – the hard part is generating the form for
the first time. to associate and form successful nuclei
4. Our lack of understanding of something should not be ascribed to
witch craft, black magic, art etc. Most of the challenges we face
result nucleation events and many things that can influence it.
I am going to later discuss a form where we knew based upon chirality that a
given form existed yet after thousands of experiments were still not able to obtain
the exceptionally more stable polymorph of a melatonin agonist

Unintentional Seeding Accounts
12
Example 2.
Xylitol – first prepared in 1891, produced as an oil for 50 years until a
new form crystallized that melted at 61°C, two years later a second
crystalline form melting at 94°C was produced, never to be able to
produce the lower melting form again.
Example 3.
Anhydrous piezeoelectric crystals of ethylene diamine tartrate produced
at industrial scale for many years until a monohydrate crystalline form
nucleated and grew preferentially at one plant site. The ―affliction‖
spread quickly to other plant sites many miles away.
(J.W. Mullins in Crystallization reprinted in 2002, pg. 200)
Coincidentally this is the same example that and
Coincidentally this is given as an example in the short book Cat's
Cradle is the fourth novel by American writer Kurt Vonnegut, first
published in 1963. Author happens to have been born in Indianapolis
and the theme of the book centers around isolation of seed crystals for a
government project. Read book or Wikipedia it (Ice nine)
name/location

13
Crystallization – An Overview
Typically viewed as a two-step process
Nucleation – Initial ordering (clustering) of molecules until
they reach a size in which further growth of the cluster
becomes thermodynamically favourable.
Crystal Growth – Further addition of molecules to the
growing nucleus (crystallite) creating the larger particles as
the crystallite increases in size in multiple directions,
sometimes faster along some axes than others.
name/location

14
Primary Nucleation (Classical Nucleation Theory)
Homogeneous nucleation
The free energy of formation of a spherical nucleus, GN, is given by the
difference between the Interfacial (I) and volume (V) excess free energy
(aka surface and the bulk),
GN = GI - GV
GI = + 4r2 and GV = - 4r3 Gvol
3
where  = interfacial free energy per unit surface area, and
where GVol = free energy change per unit volume.
GN = + 4r2 - (- 4r3 Gvol)
3
dGN = 8r + 4r2 Gvol = 0
dr
GN
* = 4 (rc
*)2
3
G
GN
*
GI
GN
GB
r
rc*
r* = critical size
GN
* = activation energy
name/location
If you have ―seed‖ crystals – you bypass
the disfavored process
Secondary Nucleation

15
An Overview
Now to a few meatier examples
Example 4.
ROY colored polymorphs of similar energy and solubility, so
tend to nucleate and grow simultaneously
Example 5.
Brief account of the Ritonavir Story
Example 6.
Account of the Missing Polymorph of the vastly more stable
polymorph of the pharmaceutically active (R- Enantiomer) of
Melatonin Agonist, whereas the inactive S-Enantiomer
readily crystallizes in the most stable form
name/location
1) Stephenson, G. A.; Kendrick, J.; Wolfangel, C.; Leusen, F. J. J. Cryst. Growth Des. 2012,12, 3964−3976.

6/21/2017 Stephenson, GA
L. Yu, G.A. Stephenson,C.A. Mitchell, C.A. Bunnell,
S. Snorek, J. Bowyer, T.B. Borchardt, J.G. Stowell,
and S.R. Byrn
Journal of the American Chemical Society (2000),
122(4), 585-591.
16
Thermochemistry and Conformational
Polymorphism of a Hexamorphic Crystal System
R P-1
mp 106.2 oC
“ROY”
ORP Pbca
OP P21/c
mp 112.7 oC
ON P21/c
mp 114.8oC
YN P-1
Y P21/c
mp 109.8 oC
N
S
H
N
O O
C
N
CH3

Ex. 4

―ROY‖ Concomitant Polymorphs – Multiple
Crystal Forms Grow Simultaneously
17
name/location
Paper by Professor Yu
Well Plate Evaporative Crystallization
(Many forms grow concomitantly)
Example 4 cont’d. Polymorphism of one of our very
important intermediates

Polymorphs Solubility Differences
and Thermodynamic Stability
18
name/location
• Pudipeddi, M., Serajuddin Trends in Solubility of Polymorphs J. PHARM. SCI. 2005, 94(5) 929-939.
Average energy difference for pairs of polymorphs is 0.33 kcal/mol for the 81
polymorphic pairs studies by Pudipeddi, M., Serajuddin
Average for 7 ROY forms is 0.14 kcal/mol
x 1.7
x 1.6
x 1.3
xxx 1.1
x 1.0
“ROY”
Solubility Ratios

19
Conformational and Color Polymorphism of 5-Methyl-2-[(2-nitrophenyl)amino]-3-
thiophenecarbonitrile. Stephenson, G. A.; Borchardt, T. B.; Byrn, S. R.; Bowyer, J.; Bunnell,
C. A.; Snorek, S. V.; Yu, L. Journal of Pharmaceutical Sciences (1995), 84(11), 1385-6.
Thermochemistry and Conformational Polymorphism of a Hexamorphic Crystal System.
Yu, Lian; Stephenson, Gregory A.; Mitchell, Christine A.; Bunnell, Charles A.; Snorek, Sharon
V.; Bowyer, J. Joe; Borchardt, Thomas B.; Stowell, Joseph G.; Byrn, Stephen R. Journal of the
American Chemical Society (2000), 122(4), 585-591.
New Polymorphs of ROY and New Record for Coexisting Polymorphs of Solved
Structures. Chen, Shuang; Guzei, Ilia A.; Yu, Lian. Journal of the American Chemical Society
(2005), 127(27), 9881-9885.
Polymorphism in Molecular Solids: An Extraordinary System of Red, Orange, and
Yellow Crystals Lian Yu
ACCOUNTS OF CHEMICAL RESEARCH, (2010), 43(9), 1257-1266.
Crystal Form Discovery of ROY
3 Forms in 1995
6 Forms in 2000
7 Forms in 2005
name/location
Up to 10 forms reported
now, though only 7 with
single crystal structures
Are These Late Appearing Polymorphs?
Are they a product of our getting further
away from the traditional conditions used
to search for polymorphs of organic
compounds

Solid Form Energy Landscape: H2O
20
name/location
One of the
oldest known
substances
15th form found
in 2009
Somewhat the old ―Number
of polymorphs being
discovered is proportional to
the time and the energy
invested in finding them‖

Example 5. A new crystal form was found in the formulated product.
This put Abbott into a market crisis. The supply of the semisolid
capsules was depleting quickly. Form II crystals were brought into our
laboratories to study its properties. Within a few days, all of the
samples that were prepared in the lab turned out to be Form II. … A
team of scientists who had been exposed to Form II visited our
manufacturing facility in Italy to investigate if any significant changes
had been made to our manufacturing process. Until this time, no
detectable quantities of Form II had been detected in the bulk drug
lots. ...soon after this visit significant amounts of Form II started
showing up in Abbott Italy bulk drug during its manufacturing process.
The origin of Form II remains debatable, the fact was that this issue
had to be addressed as soon as possible.
Chemburkar, S.R. et al. (2000). ―Dealing with the impact of Ritonavir Polymorphs on the Late
Stages of Bulk Drug Process Development". Org. Proc. Res. & Dev. 4: 413-417.
Ritanovir Story:
Nucleation and unintentional Seeding
21
name/location

Post-launch appearance of a substantially less soluble (More
Stable) Polymorphic Form of the Drug
Product recall, withdrawn from market, and reformulation
required.
Theorized that an intermediate of similar conformation nucleated
the stable polymorph.
Despite a four-fold difference in solubility, even when seeded
with the stable polymorph - Ritonavir crystallization was
sluggish. Concluded that less favored conformation (100:1) in
solution present in the stable polymorph resulted in poor
nucleation.
Bauer J, et al. (2004). "Ritonavir: An Extraordinary Example of Conformational Polymorphism".
Pharmaceutical Research 18 (6): 859–866.
Ritanovir Story:
Protease Inhibitor for Treatment of HIV
22
name/location
Late Appearing Polymorph – not a disappearing polymorph
(stable form is very sluggish nucleation and growth)
Ex. 5
Cont’d

23
name/location

24
Primary Nucleation (Classical Nucleation Theory)
Homogeneous nucleation
The free energy of formation of a spherical nucleus, GN, is given by the
difference between the Interfacial (I) and volume (V) excess free energy
(aka surface and the bulk),
GN = GI - GV
GI = + 4r2 and GV = - 4r3 Gvol
3
where  = interfacial free energy per unit surface area, and
where GVol = free energy change per unit volume.
GN = + 4r2 - (- 4r3 Gvol)
3
dGN = 8r + 4r2 Gvol = 0
dr
GN
* = 4 (rc
*)2
3
G
GN
*
GI
GN
GB
r
rc*
r* = critical size
GN
* = activation energy
name/location
If you have ―seed‖ crystals – you bypass
having to overcome the disfavored
interfacial energy term and can rely on
the favorable energy term of addition of
molecules to a post ―embryonic‖ nuclei
Secondary Nucleation

25
name/location

26
Enantiomers Produce the
Same Crystals Forms
name/location
Pasteur’s crystals of sodium ammonium tartaric acid
crystals demonstrate this nicely
Optically identified the crystals as being mirror images due
to non-superimposibiility of a facet on its crystalline face
Commenced to separate the crystals based on this
property. In his thesis in 1847. Increased our
understanding of Chirality
Just mirror image crystal forms because of mirror image
isomers
In achiral media (like most organic solvents –
mirror enantiomers should produce equivalent
forms, though of mirror image w.r.t. direction of
rotation of plane polarized light

27
Enantiomers of Melatonin Agonist
name/location
1
3
10
13
6
1
3
10
13
6
Active Enantiomer Inactive Enantiomer
1
3
10
13
6
1
3
10
13
6
Biological Systems are Chiral:
different enantiomers have
different activity and selectivity
at receptor sites
Example 6

28
Early Stage Supply Issues
name/location
Early synthesis usually at the 5-10 g scale. Many synthesis
produce racemic mixtures of enantiomers that are separated by
Liquid Chromatography using Chiral Columns
Conserve the active enantiomer for biological assays that are
specific to the enantiomer used (toxicological testing etc.)
The Lead Scientist will often choose to do early crystallization
studies using the inactive enantiomer
In theory the crystallizations should produce the same forms!
Example 6

Study of the Inactive Enantiomer
A disappearing Polymorph
three out of four initial batches were the metastable Form 1. The fourth
batch was dramatically more stable, Form 2.
Extremely difficult to produce the metastable form after discovery of the
stable Form 2
When the Active Enantiomer became available:
Never produced as the Stable Polymorphic Form 2 despite thousands of
recrystallizations and more than Ten multi kilogram scale lots!
Melatonin Antagonist
29
name/location
The compound was terminated in 1998 – I waited 14 years until it was OK to
revisit this!
Example 6

Solvent 156735 156736
acetone Form 1 Form 2
acetonitrile Form 1 oil*
ethanol Form 1 oil*
methanol Form 1 Form 2
2-propanol Form 1 Form 2
1-butanol Form 1 Form 2
ethyl acetate Form 1 Form 2
isopropyl acetate Form 1 Form 2
methyl ethyl ketone Form 1 Form 2
methylene chloride Form 1 Form 2
cumene Form 1 Form 2
n-amyl acetate Form 1 Form 2
3-methyl butanol Form 1 Form 2
toluene Form 1 Form 2
cyclohexanone oil* oil*
anisole Form 1 Form 2
methyl acetate Form 1 Form 2
n-propanol Form 1 Form 2
tetrahydrofuran Form 1 Form 2
acetic acid oil* oil**
methyl isobutyl ketone Form 1 Form 2
chloroform Form 1 Form 2
dioxane Form 1 Form 2
"wet" ethyl acetate Form 1 Form 2
Table 1. Comparative evaporative crystallization
results for the active and inactive enantiomers.
1
3
10
13
6
1
3
10
13
6
Active Enantiomer Inactive Enantiomer
1
3
10
13
6
1
3
10
13
6
30
name/location

Comparison of Physical Properties
31
Figure 7. Water solubility of MA versus temperature for crystalline forms of MA.
Property Form 1 Form 2
Density (g/cm3) 1.348 1.382
Melting point (°C) 127.9 147.0
Solubility (mg/mL) 0.4 0.1
name/location
Example 6

.
Ritonavir
(Abbott)
32
Melatonin
Agonist
x 1.7
x 1.6
x 1.3
xxx 1.1
x 1.0
“ROY”
Solubility Ratios
Contrasting Systems to ROY:
Late Appearing and Missing Polymorphs
name/location
Concomitant
Polymorph
Late
Polymorph
Relating Examples 4,5, and 6
Missing
Polymorph –
―super late‖

33
Symmetry Breaking in Crystallizations: Different Polymorphic Selection
by R- and S- Enantiomers in Achiral Media
(Missing Polymorph of the Melatonin Agonist)
name/location
1) Stephenson, G. A.; Kendrick, J.; Wolfangel, C.; Leusen, F. J. J. Cryst. Growth Des. 2012,12, 3964−3976.
Example 6

Racemate Form 1 Form 2 Hydrate
Onset Tm (°C) 136.08(0.41) 127.16(0.09) 147.39(0.08)
Enthalpy of Fusion (kJ/mol) 32.9(.25) 28.2(0.4) 36.4(0.8) NA
Density (g/cc @ 100K) 1.336 1.348 1.397 1.375
Melting Phase Diagrams Can Be Used to Establish
Racemate Relation to Polymorphs
34
name/location

Inactive Enantiomer – Apparently a disappearing Polymorph
three out of four initial batches were the metastable Form 1. The Fourth
Batch was dramatically more stable form 2.
Very difficult to produce the metastable form after discovery of the stable
Form 2
Initial Studies of Polymorphism were conducted with the inactive enantiomer
Active Enantiomer – Has never been produced as the Stable Polymorphic
Form 2 Despite thousands of recrystallizations and more than Ten multi
kilogram scale lots!
Melatonin Antagonist
Clemens, James A.; Flaugh, Michael E.; Parli, John; Sawyer, Barry D. Inhibition of luteinizing hormone
release and ovulation by 6-chloro- and 6-fluoromelatonin. Neuroendocrinology (1980), 30(2), 83-7.
Compound Patented in 1980, Discontinued Development in 1998
Just as Fascinating Today!
35
name/location
Example 6

36
Figure 2. MA crystal habits; Form 2 (top left), Form 1 (top right), Racemate (lower
left), Hydrate (lower right).
Crystal Morphologies Differ
name/location

X-ray Powder Diffraction Used Initially To Identify Forms
37
2-Theta
5 10 20 30
R-MA Form 1
RS-MA
S-MA Form 2
R-MA Monohydrate
Figure 3. Comparison of the PXRD patterns of the racemic crystal (top), chiral crystal Form 1 (upper-middle), Form 2 (lower-middle), and the monohydrate form (bottom).
name/location

Form 1 Racemate
Form 2 Hydrate
Single Crystal Diffraction: Conformational
Polymorphs, Racemate and Hydrate
38
Torsion
RS-
MA
R-MA
Form 1
S-MA
Form 2*
R-MA
H2O
T1: C2-C3-C10-C11 87.4° 99.8° 128.6° 111.1°
T2: C3-C10-C11-N12 52.3° 64.1° 160.6° 173.0°
T3: C10-C11-N12-C13 78.0° -122.2° -76.3° 101.7°
T4: C11-N12-C13-C14 175.2° 179.2° -177.8° 178.8°
name/location

39
Figure 6. 13C CPMAS Solid-State NMR spectra of crystalline forms and that of the melt of R-MA in its ―glassy-state‖,
R-MA Monohydrate, S-MA Form 2, R-MA Form 1, and the RS-MA Racemate (top to bottom).
Amorphous Form
RS-MA
S-MA Form 2
R-MA Form 1
R-MA Monohydrate
Torsion RS-MA Form 1 Form 2 Hydrate Melt Solution
C15-O6-C6-C5 (°) -0.1 3.6 9.5 -5.4
C15 Methoxy (ppm) 53.4 54.1 56.5 55.5 55.9 58.23
N12-C11-C10-C2 (°) 52.3 64.1 160.6 173
C11 methylene (ppm) 53.4 49.5 47 45.8 46.2 45.45
C16-C10-C3-C2 (°) -35.5 -23.2 1.8 -11.1
C16 methyl (ppm) 20 19.4 16.5 18.5 17.9 18.39
Table 4. Correlation of Torsion Angles with 13C Chemical Shift Values of the MA
Forms.
CP/MAS 13C Solid-State NMR used to establish
conformation in solution state
name/location

When Tf
R > Tf
A, as with Form 1 evaluated at its melting point
ΔHΦ
T
f
A = ΔHf
A - ΔHf
R + (Cl – Cs
R)(Tf
R – Tf
A) (4)
ΔSΦ
T
f
A = ΔSf
A - ΔSf
R + R ln 2 + (Cl – Cs
R)( ln Tf
R/Tf
A) (5)
ΔGΦ
T
f
A= ΔHT
f
R (Tf
A/Tf
R - 1) - Tf
A R ln 2 + (Cl – Cs
R)(Tf
R - Tf
A - Tf
A ln Tf
R/Tf
A) (6)
When Tf
A > Tf
R, as with Form 2 evaluated at its melting point
ΔHΦ
T
f
R = ΔHf
A - ΔHf
R + (Cl – Cs
A)(Tf
R – Tf
A)
ΔSΦ
T
f
R = ΔSf
A - ΔSf
R + R ln 2 + (Cl – Cs
A)( ln Tf
R/Tf
A)
ΔGΦ
T
f
R= ΔHf
A (1 - Tf
R/Tf
A) - Tf
R R ln 2 + (Cl – Cs
A)(Tf
R - Tf
A -Tf
R ln Tf
R/Tf
A) (7)
Gc = GA + RT ln 2 = RT (ln xA+ln 2) (1)
GR = RT ln xR (2)
ΔGC-R = RT (ln xA + ln 2 – ln xR) ≈ RT (ln cA/cR+ ln 2) (3)
Using Solubility Data
Using Melting Data
Tt ≈ ΔHΦ
T
f
R/ΔSΦ
T
f
R
Transition Temperature-Determined by
Extrapolation of Solubility data and/or
Thermal Data
When the Gibbs free energy curves of two forms cross, ΔG is zero
Evaluation of Thermodynamic Relationship of the Two
Polymorphs Relative to the Racemate
40
name/location

Form 1 Form 2 Racemate
Onset Tm (°C) 127.16(0.09) 147.39(0.08) 136.08(0.41)
Enthalpy of Fusion (kJ/mol) 28.2(0.4) 36.4(0.8) 32.9(.25)
Density (g/cc @ 100K) 1.348 1.397 1.336
Solubility in EtOAc (mg/mL) 184 32 18
Evaluation of Thermodynamic Relationship of the Two
Polymorphs Relative to the Racemate
Form 2 is More Stable Than Form 1
―monotropically related‖
―spontaneous resolution‖ of racemic crystal
to conglomerate at low temp
―At Constant Pressure‖
Rare!
41
In water the monohydrate converts to the
anhydrate at elevated temp
name/location

Conclusions to Melatonin Antagonist
1. Studies with the Inactive enantiomer predict that a dramatically more
stable polymorph exists for the active compound than has been
isolated
2. Indicate that over time, once nucleated, with time it will become
difficult to produce the more soluble – less stable crystalline form
Minimally it would be difficult to produce, lf not impossible to control
3. Nucleation is Extremely Important, yet still poorly understood
4. Unlike Ritonavir, the predominant conformer in solution is the same
as in the stable form
4. Heterogeneous nucleation by a chiral substance is likely responsible
for generation of stable polymorph
A Very Rare System:
A Disappearing Polymorph in one hand, A Missing Polymorph in the
other
42
name/location

.
43
Ritonavir
(Abbott)
Melatonin
Agonist
x 1.7
x 1.6
x 1.3
xxx 1.1
x 1.0
“ROY”
Solubility Ratios
Late Appearing Polymorphs
vs. Concomitant Polymorphs
name/location
0.8 kcal/mol as opposed to
0.14 kcal/mol
Late appearing polymorphs
are nearly 4 std dev away
from the average energy
difference for organic
polymorphs!

Conclusions to Melatonin Antagonist
The primary nucleation rate for the stable polymorph is much slower
than that of the metastable form due to its exceptional
thermodynamic stability (much greater entropic cost of surface
formation). Like ritonavir, in the absence of heterogeneous
nucleation by an appropriate substance, its late appearance
(induction time) may become prohibitively long.
The pair-wise study of the crystallization of enantiomeric substances
may lead to new understanding of primary nucleation because it
affords the researcher an opportunity to approach crystallization of a
given form twice (free of homogeneous primary nucleation)
44
name/location

Disappearing Polymorphs
45
―We believe that once a particular polymorph has been
crystallized it is always possible to obtain it again; it is
only a matter of finding the right experimental
conditions.‖
Disappearing Polymorphs Dunitz, J.D.; Bernstein, Acc. Chem. Res.
1995, 28, 193-200.
Because of the appearance of secondary nuclei, the difficulty of
obtaining a given stable crystalline form has been removed by the
nuclei making it very difficult for the metastable crystal form to
compete – hence it becomes much more difficult to obtain the
metastable form reproducibly in high purity and quantity
name/location

Concomitant, Disappearing, and Late
appearing Polymorphs
46
With concomitant polymorphs like ROY, the solubilities (and GB) are
similar such that the nucleation rates GN dictate the outcome of the
crystallization that often results in mixtures of forms. Dr. Yu has some very
good examples and explanations in his work.
Because of the appearance of secondary nuclei, the difficulty of
obtaining a given metastable crystal form with a high degree of
reproducibility may be severely compromised. This might be
analogous to
Ritonavir, is a late appearing polymorph, but not truly a disappearing
polymorph. While the GB is substantially more favorable (less
soluble) relative to the initial form discovered. On the other hand, its
rate of nucleation is extremely slow relative to the initial form. As a
result, the metastable form can still be produced.
name/location

Thank You
Dr. Ann Newman 7th Street Development Group
Crystal Pharmatech (Dr. Alex Chen Dr. Bob Wenslow, Dr. Yanfeng Zhang) for their
continued support of advancement of the solid-state pharmaceutical sciences and their
support of this webinar series
Dr. Lian Yu, for the good collaboration over the years on ROY and other projects
Eli Lilly and Company for allowing me to work on so many interesting problems over my
27 years and the wonderful scientists that I enjoyed working with along the way
You, the audience for your time
47
name/location

Webinar Disappearing Polymorphs Stephenson 7th St Dev Group 6-21-17.pdf

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Webinar Disappearing Polymorphs Stephenson 7th St Dev Group 6-21-17.pdf