Polymorphs, Solvates and Phase Relationships: Some Perspectives

1
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

2
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

3
Some advice to lecturers I once read
but cant 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.

4
What is the current status of this field of
research in polymorphs/crystal forms/phase
relationships?
5
Walter C. McCrone 1916-2002
6
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, 911-29 (1969).
7
The Current Status?
Meeting room for a conference on polymorphism
ca. 1964
Meeting room for a conference on polymorphism
2004
8
The three most important factors to consider when
buying real estate

• LOCATION

• LOCATION

• LOCATION

Buy land theyre not making any more of
it. - Will Rodgers
9
The three most important factors in doing
research on crystal forms

• CONTROL

• CONTROL

• CONTROL

10
Were going to talk about how you control
crystal nucleation and growthcontrol at the
nucleation stage. Les - Erice, June 15, 2004
If they havent 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
11
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 ones 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).
12
Disappearing polymorphs, contd...

• 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.

13
Disappearing polymorphsAn old example
benzophenone
14
Schaeling gains control
Here in brief are some remarks about working
with the meta-stable modification. It requires
some practice. We observed that the metastable
benzophe-none we obtained from the melt heated to
a high temperature could be induced to yield
crys-tals 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 possi-
ible 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.
15
Disappearing Polymorphs Benzocaine
Picric Acid

• 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

16
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)
17
The Ritonavir Story
18
Ritonavir - The Problem

• the FDA have seen similar problems before
  with other products.

• polymorphismis the problem were experiencing
  with ritonavir

• After two-and-a-half years of closely monitored
  and testedformulation manufacturing, we
  encountered a new form of ritonavir, a crystal
  form...Previous to May-June 1998 we had
  manufactured about 240 batches of ritonavir and
  none of those batches had ever failed a
  dissolution test.

19
Ritonavir - The Problem (contd)

• 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.

20
Ritonavir - The Consternation

• There was no gradual trend. Something occurred
  that that caused the new form to occurThere 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
  itForm II is new.

21
Ritonavir - The Consternation (contd)

• 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 didnt know how to prevent it.
  And we kept asking the question, why now?We did
  not know the physical properties of the new
  formWe 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.

22
Ritonavir - Attempts to Resolve the Problem

• While we have speculated on the cause of this
  chemical transformation, we dont have conclusive
  proof what happenedAbbott could not solve the
  problem for reasons which now are more apparent
  than they were when the problem was first
  discoveredThermodynamics govern everything we do
  in the pharmaceutical industry.

23
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.

24
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 worldto 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.

25
Ritonavir - Incredulity and Unpredictability

• Q You are a large multinational company. Your
  scientists are obviously smart. How could this
  happen?

A A companys size and the collective IQs of
their scientists have no relationship to this
problemThis obviously has not happened to every
drug. But it has happened to other drugs.
26
Ritonavir - The solution proposed
27
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 capsulesNorvir
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.
28
The Ritonavir Story -
The Ultimate Loss of Control?
29
Ritonavir - The Problem

• the FDA have seen similar problems before
  with other products.

Its 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.
30
Ritonavir - The Problem

• polymorphismis the problem were experiencing
  with ritonavir

Problem? Perhapsbut also a challenge to our
scientific imagination and acumen and an
opportunity to improve properties and gain some
intellectual property.
31
Ritonavir - The Problem

• After two-and-a-half years of closely monitored
  and testedformulation manufacturing, we
  encountered a new form of ritonavir, a crystal
  form...Previous to May-June 1998 we had
  manufactured about 240 batches of ritonavir and
  none of those batches had ever failed a
  dissolution test.

They didnt predict it, they didnt expect it and
they didnt 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.
32
Some ways to avoid this problem

• Thorough characterization
• Yu, Reutzel-Edens, Griesser, Henck, Bugay, KR
  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
33
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).
34
Acetaminophen/paracetamol (Tylenol)

• Recalculation of the lattice energeticsestablish
  ed 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.
35
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 youve got to do the experiment again.
Roj - Erice, June 15, 2004
36
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).
37
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).
38
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

39
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
40
Paracetamol recrystallised from methanol at 0.6
GPa to give a new 11 methanol solvate
41
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?
42
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
43
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 Boldyrevas study on
  
• powder (no grinding) and interconversion is
  complete
• kinetic barriers associated with interconversion
  reduced

demonstration that metastable phases can be
prepared
44
4. Parabanic Acid
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."
45
Ritonavir - The Problem (contd)

• 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
46
Ritonavir - The Consternation

• There was no gradual trend. Something occurred
• that caused the new form to occurThere 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.
47
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
  itForm II is new.

• Nature does, in fact, favor more stable forms
• Essentially restatement of Ostwalds Rule of
  Stages
• Davey

48
Ritonavir - The Consternation (contd)

• 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 didnt know how to prevent it.
  And we kept asking the question, why now?We did
  not know the physical properties of the new
  formWe 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.
49
Ritonavir - The Consternation (contd)

• 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 didnt know how to prevent it.
  And we kept asking the question, why now?We did
  not know the physical properties of the new
  formWe 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
50
Ritonavir - The Consternation (contd)

• 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
51
Ritonavir - Attempts to Resolve the Problem

• While we have speculated on the cause of this
  chemical transformation, we dont have conclusive
  proof what happenedAbbott 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
52
Ritonavir - Attempts to Resolve the Problem

• While we have speculated on the cause of this
  chemical transformation, we dont have conclusive
  proof what happenedAbbott could not solve the
  problem for reasons which now are more apparent
  than they were when the problem was first
  discoveredThermodynamics 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!!
53
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.

Weve also been here seven days a week, but
(fortunately!) wont continue to do so.
54
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!
55
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 worldto 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.
56
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
wouldnt have gotten into this mess
57
Ritonavir - Incredulity and Unpredictability
A A companys size and the collective IQs of
their scientists have no relationship to this
problemThis obviously has not happened to every
drug. But it has happened to other drugs.
And when it happens again, youll be ready
58
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?

59
Occurrence of Polymorphism
Oft-quoted McCrone statement

• every compound has different polymorphic forms
  andthe 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).

60
Some BUTs

• Naphthalene

Sucrose
Perylene red Erk
61
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)

62
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

63
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.

64
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
65
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

• Dont hesitate to use unconventional measures,
  e.g. pressure

• Potential for new technologies, e.g.
  combinatorial chemistry high throughput
  technology

• If it works, its fair game

66
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?

67
Physical and chemical properties that may vary
among polymorphs (partial list)

• molecular conformation
• photochemical reactivity
• thermal stability
• filtration and drying characteristics
• dissolution rate
• bioavailability

• melting point
• vapor pressure
• hardness
• optical, electrical, magnetic properties
• color
• IR spectra
• NMR spectra

68
Polymorphs are most often recognized because of
the difference in properties
but these properties can also be quite similar.
69
Melting point

• Benzocaine picric acida

• D-Mannitolb

Form I Form II
130-132 ºC
166.5 ºC
162-163 ºC
166 ºC
aJ.-O. Henck, et al., J. Am. Chem. Soc, 123, 1834
( 2001).
bM. Burger, et al., J. Pharm. Sci. 80, 457 (2000).
70
Similar IR spectra
Two polymorphs of caffeinea
aU. Griesser, personal communication
71
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
72
Polymorphism in molecular complexes
Two polymorphs of TMTSF and TCNQ
Red Form
Black Form
73
Polymorphism and electrical conductivity of
molecular complexes
Two polymorphs of TMTSF and TCNQ
Red Form Mixed stacks
Black Form Segregated stacks
74
Comparison of Red and Black Forms of TMTSFTCNQ
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

• opaque

• mixed stacks

• segregated stacks

• semiconductor

• conductor

75
But there are limits another complex

• Concomitant a and b polymorphs from benzene by
• slow cooling
• prolonged slow evaporation

76
Structures and electrical properties
b - c-axis stacks offset
a - vertical stacks

• 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

77
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).

78
Colors in ROY
5-Methyl-2-(2-nitro-phenylamino)- thiophene-3-carb
onitrile

• 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)
79
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).
80
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).
81
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?

82
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
83
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
84
The End