Polymorphs, Solvates and Phase
Relationships:
Some Perspectives
Joel Bernstein
Ben-Gurion University of the Negev
DIVERSITY AMIDST SIMILARITY:
A Multidisciplinary Approach
to
Polymorphs, Solvates and Phase Relationships
Erice, Sicily
June 19, 2004
Polymorphs, Solvates and Phase
Relationships:
Some (Personal) Perspectives
Joel Bernstein
Ben-Gurion University of the Negev
DIVERSITY AMIDST SIMILARITY:
A Multidisciplinary Approach
to
Polymorphs, Solvates and Phase Relationships
Erice, Sicily
June 19, 2004
Some advice to lecturers I once read…
…but can’t remember where:
“ People like to hear what they already
know. Plan your talk so it contains about
35-45% of material your audience is
already familiar with.”
What is the current status of this
field of research in polymorphs/
crystal forms/phase relationships?
Walter C. McCrone 1916-2002
Two landmark McCrone papers
“Polymorphism” , in Physics and Chemistry of the Organic
Solid State, Vol. 2, Wiley Interscience (1965), pp. 726-767.
“Pharmaceutical Applications of Polymorphism”, (with J.
Haleblian), in Journal of Pharmaceutical Sciences, 58, 91129 (1969).
The Current Status…?
Meeting room for a conference
on polymorphism ca. 1964
Meeting room for a conference
on polymorphism 2004
The three most important factors to
consider when buying real estate:
 LOCATION
 LOCATION
 LOCATION
“Buy land; they’re not making any more of it.”
- Will Rodgers
The three most important factors in
doing research on crystal forms:
CONTROL
CONTROL
CONTROL
“We’re going to talk about how you control
crystal nucleation and growth…control at the
nucleation stage.”
Les - Erice, June 15, 2004
“If they haven’t defined and controlled their
crystallisation experiments they can run into
disappearing polymorphs.”
“Roj” - Erice, June 15, 2004
“Know what you have….Make the same thing
every time.”
Steve Byrn - Erice, June 18, 2004
Disappearing Polymorphs
…it may be important to obtain a particular polymorph under
controlled and reproducible conditions. However, this is not
always easy to achieve. Tales of difficulties in obtaining
crystals of a particular known form or in reproducing results
from another laboratory (or even 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…
Dunitz and Bernstein, Accts. Chem Res. 28, 193 (1995).
Disappearing polymorphs, cont’d...
“…What is disturbing about the phenomenon of
disappearing or elusive polymorphs is the apparent loss of
control over the process: we did the experiment last week
and got the result, and now we cannot repeat it! This kind
of statement can lead to raised eyebrows or even to
expressions of disbelief. We have ourselves experienced
the frustration of not being able to reproduce an
experimental result that was undoubtedly obtained
earlier.”
Disappearing polymorphs:
An old example: benzophenone
Schaeling gains control…
Here in brief are some remarks
about working with the metastable modification. It requires
some practice. We observed
that the metastable benzophenone we obtained from the melt
heated to a high temperature
could be induced to yield crystals of the stable form only by
introducing seeds of the stable
form. The metastable form is
very sensitive to the presence
of the stable form. It was possiible to keep the metastable form open only in a room which was absolutely clean. It was
almost impossible to carry out experiments on the metastable modification in a room
which had previously “seen” the stable form, because the hands of [the experimenters]
and the equipment in the laboratory were poisoned with the stable modification. The
solution to this problem was to change the room and start the experiments once again
from the start.
Disappearing Polymorphs:
Benzocaine : Picric Acid
O2N
O
H2N
CH3
O
C
H2
HO
NO2
O2N
 low-melting (132ºC) form used as a
pharmacopeial standard
 higher melting (162-163 ºC) form obtained by drying
low melting form at 105 ºC for at least 1 hour or by
vacuum drying/sublimation
 Once latter form had been obtained,
lower melting form could no longer be prepared
How the authors regained control...
“As a matter of curiosity, it ought to be mentioned
that once the stable modification was obtained, the
metastable modification could no longer be isolated…
It was found that after discarding all samples, washing
the equipment and laboratory benches and waiting for
8-12 days, the low-melting modification could be
isolated again. This has now been repeated several
times in our laboratories.”
Nielsen and Borka, Acta Pharm. Suecica 9, 503 (1972)
The Ritonavir Story
Ritonavir - The Problem
“…[the FDA] have seen similar problems before with
other products.”
“…polymorphism…is the problem we’re experiencing
with ritonavir…”
“After two-and-a-half years of closely monitored and
tested…formulation manufacturing, we encountered a
new form of ritonavir, a crystal form...Previous to [MayJune 1998] we had manufactured about 240 batches
of ritonavir and none of those batches had ever failed
a dissolution test.”
Ritonavir - The Problem (cont’d)
“What has happened is that a new crystal form of
ritonavir has appeared. Although it has the same
purity, this form has different properties that make it
more difficult to formulate. Specifically, the crystalline
structure makes ritonavir dissolve more slowly…,
which affects its bioavailability.”
Ritonavir - The Consternation
 “There was no gradual trend. Something occurred
that that caused the new form to occur…There was
no early warning.”
“We, quite honestly, have not been able to pinpoint
the precise conditions which led to the appearance of
the new crystal form. We now know that the new form
is, in fact, more stable than the earlier form, so nature
would appear to favor it…Form II is new.”
Ritonavir - The Consternation (cont’d)
“We did not know how to detect the new form. We did
not know how to test for it. We did not know what
caused it. We didn’t know how to prevent it. And we
kept asking the question, why now?…We did not
know the physical properties of the new form…We
did not know how to clean it, and we did not know
how to get rid of it.”
“…our initial activities were directed toward
eliminating Form II from our environment. Then we
finally accepted that we could not get rid of Form II.
Then our subsequent activities were directed to
figuring out how to live in a Form II world.”
Ritonavir - Attempts to Resolve the
Problem
 “While we have speculated on the cause of this
chemical transformation, we don’t have conclusive
proof what happened…Abbott could not solve the
problem for reasons which now are more apparent
than they were when the problem was first
discovered…Thermodynamics govern everything we
do in the pharmaceutical industry.”
Ritonavir - Attempts to Resolve the
Problem
 “This is why all of us at Abbott have been working
extremely hard throughout the summer, often around
the clock, and sometimes never going home at night.
We have been here seven days a week and we will
continue to do so. We have canceled vacations and
asked our families for their understanding and
support. This is not an issue that we take lightly.”
 “There were several sub-teams of three to 600 people
per team working full time in different areas. We also
called on as many resources as we could.”
Ritonavir - More attempts...
 “We tried everything. We conducted countless
experiments. We reconditioned our facilities. We
rebuilt facilities and new lines. We looked at
alternative sites. We visited a number of [other]
organizations around the world…to see if we could
start clean in a new environment free of Form II.”
 “In a matter of weeks – maybe five or six weeks,
every place the product was became contaminated
with Form II crystals.”
Ritonavir - Incredulity and Unpredictability
Q: You are a large multinational company. Your
scientists are obviously smart. How could this
happen?
A: A company’s size and the collective IQ’s of their
scientists have no relationship to this
problem…This obviously has not happened to
every drug. But it has happened to other drugs.
Ritonavir - The solution proposed
Ritonavir - The solution approved
Abbott Laboratories Receives U.S. FDA
Approval for Reformulated Norvir
(ritonavir) Capsule
New Soft-Gelatin Capsules Offer Non-Refrigerated,
Twice-Daily Treatment Option
ABBOTT PARK, Ill., June 30, 1999 - Abbott Laboratories announced today it has
received U.S. Food and Drug Administration (FDA) approval for Norvir (ritonavir)
soft-gelatin capsules…Norvir soft-gelatin capsules require refrigerated storage between
36-degrees F to 46-degrees F until dispensed to patients…
The approval of Norvir soft-gelatin capsules follows intense reformulation work at
Abbott after an announcement in July 1998 that a new crystalline structure of ritonavir,
which affected how the semi-solid capsule dissolved, would interrupt the production of
Norvir semi-solid capsules.
The Ritonavir Story - The Ultimate Loss of Control?
Ritonavir - The Problem
“…[the FDA] have seen similar problems before with
other products.”
It’s not a new phenomenon, but every instance of
multiple crystal forms is new and unique, and
each case is one which we have to fully
investigate, characterize, control and properly
educate and inform the regulatory agencies.
Ritonavir - The Problem
“…polymorphism…is the problem we’re
experiencing with ritonavir…”
Problem?
Perhaps…but also a challenge to our
scientific imagination and acumen and an
opportunity to improve properties and gain
some intellectual property.
Ritonavir - The Problem
“After two-and-a-half years of closely monitored and
tested…formulation manufacturing, we encountered a
new form of ritonavir, a crystal form...Previous to [MayJune 1998] we had manufactured about 240 batches
of ritonavir and none of those batches had ever failed
a dissolution test.”
They didn’t predict it, they didn’t expect it and
they didn’t want it.
Caveat on the most stable form: If they had
discovered this form before launch they may have
abandoned the drug because of poor bioavailability.
Some ways to avoid this problem:
 Thorough characterization
Yu, Reutzel-Edens, Griesser, Henck, Bugay, K&R Harris,
Niemczyk, etc.
 High throughput technology
Morissette, Wu, Dova, etc.
Combination of computational and
experimental exploration of “crystal form”
space
Gavezzotti, Price, Pulham, Davey, Leiserowitz, Boese, Brill,
Henck, Griesser, etc.
Know your system thoroughly
Bugay, Byrn, Clas
Acetaminophen/paracetamol (Tylenol®)
Two well characterized forms:
 Commercial Form I requires binders for
formulation
 Form II can be directly compressed but
transforms to Form I
e.g. G. Nichols et al., J. Pharm. Sci. 87, 684 (1998).
Acetaminophen/paracetamol
(Tylenol®)
“Recalculation of the lattice
energetics…established that this third
structure is actually too unstable to exist.”
P. Verwer and F.J.J. Leusen, “Computer Simulation to
Predict Possible Crystal Polymorphs”, Revs. Comp. Chem.
Vol. 12, Wiley, (1998) pp. 327-365.
A Philosophical Digression
“But not to be able to find something is no
proof of its nonexistence.”
J.-F. Revel and M. Ricard, “The Monk and the
Philosopher”, Thorsons, 1998, p. 57.
“If you repeat an experiment and only get
one form, then you’ve got to do the
experiment again.”
“Roj” - Erice, June 15, 2004
Acetaminophen/paracetamol
(Tylenol®)
 Third form detected by microscopy
Griesser, etc.
A. Burger et al., Acta Pharm. Technol. 28, 1-20 (1982);
P. Di Martino et al., J. Therm. Anal.48, 447-458 (1997);
M. Szwlagiewicz et al., ibid 57, 23-43 (1999).
 Third form calculated and predicted from a
number of similar energy possibilities
Gavezzotti, Price, Lu, Henck, etc.
T. Beyer et al., J. Am. Chem. Soc. 123, 5086-5094 (2001).
Acetaminophen/paracetamol
(Tylenol®)
 Third form produced by iterative high
throughput technology
Morissette, Wu, Dova, etc.
 Characterized by microscopy and Raman
Griesser, Bugay
 X-ray powder pattern closely matches one of
the less likely but possible structures of
Beyer et al.
K. Harris, David
M.L. Peterson et al., J. Am. Chem. Soc. 124, 10958-10959 (2002).
6.
Paracetamol (Acetaminophen)
• Widely used analgesic drug
• Exists as stable monoclinic form and metastable
orthorhombic form
• A monohydrate and two trihydrates recently prepared
at ambient pressure
A. Parkin, S. Parsons and C.R. Pulham, Acta Cryst. 2002, E58, 1345-1347.
P.A. McGregor, D.R. Allan, S. Parsons and C.R. Pulham, J. Pharm. Sci., 2002, 91,1308-1311.
But still have no way of predicting
solvates and hydrates…
…although we might look for computed
and other forms using high pressure.
Gavezzotti, Price, Katrusiak, Pulham
Paracetamol recrystallised from methanol at 0.6 GPa
to give a new 1:1 methanol solvate
Single crystal of
the solvat e
Tungsten gasket
Methanol
sol vent
Ruby chip
200 mm
F.P.A. Fabbiani, D.R. Allan, A.D. Dawson,
W.I.F. David, P.A. McGregor, I.D.H. Oswald,
S. Parsons, and C.R. Pulham,
Chem. Commun. (2003), 3004-3005.
Paracetamol recrystallised from water at 1.1 GPa
to give a new dihydrate
On decompression crystal dissolves
rather than disintegrates - scope for
isolation of dihydrate at ambient
pressure?
But still have no way of predicting
solvates and hydrates…
…although we might look for computed
and other forms using high pressure.
Katrusiak, Pulham
Some of these might be metastable at
ambient conditions.
Pulham, Yu, Henck, Davey, Leiserowitz
Can metastable phases be isolated?
Or, more importantly, can we co-crystallise paracetamol and
ethanol?!!
Recrystallisation of monoclinic paracetamol from ethanol
at 1.1 GPa gives the metastable orthorhombic polymorph,
recoverable at ambient pressure.
• much lower pressure than in Boldyreva’s study on
powder (no grinding) and interconversion is complete
• kinetic barriers associated with interconversion reduced
demonstration that metastable phases can be prepared
4.
Parabanic Acid
O
H
H
N
O
N
O
Analogue of barbituric acid.
Structural studies have shown that
one of the oxygen atoms does not
take part in hydrogen bonding.
A recent computational study correctly
reproduced the known experimental
crystal structure as the global minimum
in the lattice energy.
Calculations also identified seven other hypothetical structures that lie
only 2-6 kJ mol-1 higher in energy than the known form.
"it is unlikely that additional polymorphs of parabanic acid will be readily
found as persistent metastable forms."
X. M. He, S. Swaminathan, B. M. Craven, R. K. McMullan, Acta Cryst., 1988, B44, 271.
T.C. Lewis, D.A. Tocher, G.M. Day, and S.L. Price, CrystEngComm., 2003, 5, 3.
Ritonavir - The Problem (cont’d)
“What has happened is that a new crystal form of
ritonavir has appeared. Although it has the same
purity, this form has different properties that make it
more difficult to formulate. Specifically, the crystalline
structure makes ritonavir dissolve more slowly…,
which affects its bioavailability.”
Thermodynamics and structure-property relations
Herbstein, Yu, Reutzel-Edens, Henck, Bugay, Niemczyk. Davey, Leiserowitz,
Morissette, Ward, Byrn
Ritonavir - The Consternation
 “There was no gradual trend. Something occurred
that caused the new form to occur…There was no
early warning.”
Many discoveries of new crystal forms are serendipitous,
and it is often difficult, if not impossible, to precisely
recreate the conditions at the time of the formation of the
new form.
Ritonavir - The Consternation
“We, quite honestly, have not been able to pinpoint
the precise conditions which led to the appearance of
the new crystal form. We now know that the new form
is, in fact, more stable than the earlier form, so nature
would appear to favor it…Form II is new.”
-Nature does, in fact, “favor” more stable forms
-Essentially restatement of Ostwald’s Rule of Stages
Davey
Ritonavir - The Consternation (cont’d)
“We did not know how to detect the new form. We did
not know how to test for it. We did not know what
caused it. We didn’t know how to prevent it. And we
kept asking the question, why now?…We did not
know the physical properties of the new form…We
did not know how to clean it, and we did not know
how to get rid of it.”
Detect and test: Reutzel, Griesser, Henck, Niemczyk, Harris, Bugay, Harris,
David, Morissette, etc.
Caused: ???
Prevent: Henck, Davey, Leiserowitz
Physical properties: Herbstein, Yu, Reutzel, Griesser, Henck, Niemczyk, Harris,
Bugay, Harris, David, Morissette, Byrn, Erk, Schmidt, Ward,
Nassembeni, Clas, etc.
Ritonavir - The Consternation (cont’d)
“We did not know how to detect the new form. We did
not know how to test for it. We did not know what
caused it. We didn’t know how to prevent it. And we
kept asking the question, why now?…We did not
know the physical properties of the new form…We
did not know how to clean it, and we did not know
how to get rid of it.”
Why now? Nobody knows
How to clean it; how to get rid of it: Henck, Davey, Leiserowitz
Ritonavir - The Consternation (cont’d)
“…our initial activities were directed toward
eliminating Form II from our environment. Then we
finally accepted that we could not get rid of Form II.
Then our subsequent activities were directed to
figuring out how to live in a Form II world.”
“…how to live in a Form II world”:
Herbstein, Yu, Henck, Davey, Leiserowitz, Bugay, etc
Ritonavir - Attempts to Resolve the
Problem
 “While we have speculated on the cause of this
chemical transformation, we don’t have conclusive
proof what happened…Abbott could not solve the
problem for reasons which now are more apparent
than they were when the problem was first
discovered...”
It took them a year to learn what you have learned in ten
days
Ritonavir - Attempts to Resolve the
Problem
 “While we have speculated on the cause of this
chemical transformation, we don’t have conclusive
proof what happened…Abbott could not solve the
problem for reasons which now are more apparent
than they were when the problem was first
discovered…Thermodynamics govern everything we
do in the pharmaceutical industry.”
Thermodynamics… Herbstein, Yu, Henck, Reutzel, Griesser, Katrusziak,
Pulham, Davey, Leiserowitz, Byrn, Coquerel, Descamps
Tell that to your second year chemistry/pharmacy
students!!
Ritonavir - Attempts to Resolve the
Problem
 “This is why all of us at Abbott have been working
extremely hard throughout the summer, often around
the clock, and sometimes never going home at night.
We have been here seven days a week and we will
continue to do so. We have canceled vacations and
asked our families for their understanding and
support. This is not an issue that we take lightly.”
We’ve also been here seven days a week, but (fortunately!) won’t
continue to do so.
Ritonavir - Attempts to Resolve the
Problem
 “There were several sub-teams of three to 600
people per team working full time in different
areas. We also called on as many resources as
we could.”
Now they can hire all Erice Poly 2004 as consultants!
Ritonavir - More attempts...
 “We tried everything. We conducted countless
experiments. We reconditioned our facilities. We
rebuilt facilities and new lines. We looked at
alternative sites. We visited a number of [other]
organizations around the world…to see if we could
start clean in a new environment free of Form II.”
 “In a matter of weeks – maybe five or six weeks,
every place the product was became contaminated
with Form II crystals.”
If they had thought more carefully about seeds they might
have avoided at least some of these problems.
Ritonavir - Incredulity and Unpredictability
Q: You are a large multinational company. Your
scientists are obviously smart. How could this
happen?
If their scientists had attended “Diversity amidst
Similarity - Erice Poly 2004” maybe they wouldn’t
have gotten into this mess…
Ritonavir - Incredulity and Unpredictability
A: A company’s size and the collective IQ’s of their
scientists have no relationship to this
problem…This obviously has not happened to
every drug. But it has happened to other drugs.
And when it happens again, you’ll be ready…
The General Situation
 What is the frequency of occurrence of
polymorphism and/or different crystal forms?
 How do we prepare different crystal forms in
a controlled and reproducible manner?
 What are the similarities and differences of
properties of the different crystal forms?
Occurrence of Polymorphism
Oft-quoted McCrone statement
“…every compound has different
polymorphic forms and…the number of
forms known for a given compound is
proportional to the time and energy spent in
research on that compound.”
W. C. McCrone, in Physics and Chemistry of the Organic
Solid State, Vol. 2, Wiley Interscience (1965).
Some “BUT’s”
Naphthalene
Perylene red: Erk
Sucrose
Less quoted statement
“With the accumulation of data there is
developing a gradual realization of the
generality of polymorphic behavior, but to
many chemists polymorphism is still a
strange and unusual phenomenon.”
M.J. Buerger and M.C. Bloom, Zeit. Fur Krist. A96, 182 (1937)
Occurrence of polymorphism in molecular
crystals
 Not all polymorphs have structures reported; very
often information is in primary literature as
opposed to data bases
 Problems locating all forms; definition by
author(s)
 Not always
recognized
 Statistics are difficult to determine
 Existence of multiple crystal forms is not unusual
Occurrence of polymorphism in molecular
crystals
The existence of more than one crystal form
(polymorphs and/or solvates) of any substance is not
obvious and is not yet predictable. However, it is not
surprising when new crystal forms are discovered, either
by systematic searching, or by serendipity.
 Keep eyes and mind open, even if not involved in a
conscious effort to prepare new crystal forms.
The General Situation
 What is the frequency or occurrence of
polymorphism and/or different crystal forms?
 How do we prepare different crystal forms in
a controlled and reproducible manner?
Many suggestions from many speakers
Some suggestions for preparing different crystal
forms in a controlled manner
 Use thermal information from microscopy and DSC/TGA to
determine trial conditions for crystal growth
 Try kinetic as well as thermodynamic conditions
 Use molecular and crystal structural data to generate crystallization
conditions (solvent, solvent mixtures and ‘tailor-made’ additives) to
prevent or induce particular forms
 Avoid seeds of undesired forms, but use seeds of desired forms
 Be aware of literature and use it
 Don’t hesitate to use unconventional measures, e.g. pressure
 Potential for new technologies, e.g. combinatorial chemistry; high
throughput technology
 If it works, it’s fair game
The General Situation
 What is the frequency or occurrence of
polymorphism and/or different crystal forms?
 How do we prepare different crystal forms in
a controlled and reproducible manner?
 What are the similarities and differences of
properties of the different crystal forms?
Physical and chemical properties that may
vary among polymorphs (partial list)
melting point
vapor pressure
hardness
optical, electrical,
magnetic properties
color
IR spectra
NMR spectra
molecular conformation
photochemical reactivity
thermal stability
filtration and drying
characteristics
dissolution rate
bioavailability
Polymorphs are most often recognized
because of the difference in properties…
…but these properties can also be quite
similar.
Melting point
Benzocaine : picric acida
aJ.-O.
bM.
D-Mannitolb
130-132 ºC
Form I
166.5 ºC
162-163 ºC
Form II
166 ºC
Henck, et al., J. Am. Chem. Soc, 123, 1834 ( 2001).
Burger, et al., J. Pharm. Sci. 80, 457 (2000).
Similar IR spectra
Two polymorphs of caffeinea
aU.
Griesser, personal communication
Structure-property relations
Two strategies for studying structure-property
relations:
Maximize the number of observations
 Minimize the number of variables
The number of variables can be minimized by
studying polymorphic systems, since only the
structure varies
Polymorphism in molecular complexes
Two polymorphs of TMTSF and TCNQ
Me
Se
Se
Me
Red Form
Se
Se
Me
Me
NC
CN
NC
CN
Black Form
Polymorphism and electrical conductivity of
molecular complexes
Two polymorphs of TMTSF and TCNQ
Me
Se
Se
Me
Red Form
Mixed stacks
Se
Se
Me
Me
NC
CN
NC
CN
Black Form
Segregated stacks
Comparison of Red and Black Forms of
TMTSF:TCNQ
Red Form
Black Form
from CH3CN by slow
evaporation
from CH3CN by rapid
cooling of saturated
solution; use seeds for
larger crystals
 thermodynamic
crystallization
 kinetic crystallization
 transparent
 mixed stacks
 opaque
 semiconductor
 segregated
stacks
 conductor
But there are limits…
…another complex:
NH2
O
Cl
Cl
Cl
Cl
O
NH 2
Concomitant a and b polymorphs from benzene by
 slow cooling
 “prolonged slow evaporation”
Structures and electrical properties
a - vertical stacks
b - c-axis stacks offset
Raise T of a form electrical conductivity rises by 107
Also upon formation of pellet
IR spectra identical before and after
no structural change by X-ray
ESR, SSNMR provide no clues
The “explanation”….
“…no ordinary conduction mechanism can
rationalize the low resistivity value of the
low resistance a form.”
Goto et al., Bull. Chem. Soc. Japan, 69, 85 (1996).
Colors in “ROY”
5-Methyl-2-(2-nitro-phenylamino)thiophene-3-carbonitrile
 Differences in color can be accounted for from differences
in conformation
 Molecular property - can consider crystal as ‘oriented gas’
L. Yu J. Phys. Chem. A106, 544-550 (2002)
“Chromoisomerism” of 9-Phenylacridinium
Hydrogen Sulfate
 Red and green crystal forms
 Crystal structures carried out; other spectroscopic
characterization
P.H. Toma et al., Chem, Mater. 6, 1317-1324 (1994).
“Chromoisomerism” of 9-Phenylacridinium
Hydrogen Sulfate
 Diffuse reflectance spectra of powders, coupled with
INDO calculations, did not identify the origin of the
color difference.
 “…it does not become obvious why one [polymorph] is
red and the other is green. Chromisomerism in this case is
just as puzzling to [us] as it was to Hantszsch and his
colleagues 80 years ago… must consider collective
interactions”.
 Many crystal forms recognized by difference in color.
 Eye is a sensitive detector; seeing is not necessarily
understanding.
P.H. Toma et al., Chem, Mater. 6, 1317-1324 (1994).
The General Situation
 What is the frequency or occurrence of
polymorphism and/or different crystal forms?
 How do we prepare different crystal forms in
a controlled and reproducible manner?
 What are the similarities and differences of
properties of the different crystal forms?
Closing quotation…
“There are many mysteries of nature that we have not solved.
Hurricanes, for example, continue to occur and often cause
massive devastation. Meteorologists can not predict months in
advance when and with what velocity a hurricane will strike a
specific community. Polymorphism is a parallel phenomenon.
We know that it will probably happen. But not why or when.
Unfortunately, there is nothing that we can do today to prevent a
hurricane from striking any community or polymorphism from
striking any drug.”
Dr. Eugene Sun, Abbott Laboratories, 1998
Closing, closing quotation
“Many people think that polymorphism and
solid state chemistry is the hardest thing to get
right in drug development.”
- Steve Byrn, Erice, June18, 2004
The End