882 RESONANCE September 2009

GENERAL ARTICLE
Polymorphism: An Overview
Rahul Purohit and P Venugopalan
Keywords
Polymorphism, phasetransition,
i ntermolecul ar i nteractions,
monotropes, enantiotropes.
It is quite common for the same material to crystallize in
different arrangements of the molecules in the crystal. This
phenomenon is referred to as polymorphism and it happens
for elements, pharmaceuticals, biological compounds and
proteins. In this article we present a brief review of polymor-
phism, stressing its physical aspects, types and applications.
We discuss why it is important to understand the phenom-
enon, and the need to develop ways of controlling it. We also
outline some legal issues related to it.
The gross property differences between graphite and diamond is
known even to a high school student: In fact, this example is
taught as a typical case of how structure determines properties.
Chemists were cognizant of many such examples of structure
property relationships even while chemistry was in its incipient
stage. Today, most students of science would have deeply im-
bibed this sentence Graphite and diamond are allotropes. They
are aware that elements have allotropes and this phenomenon is
defined as allotropism. What about compounds? The present
article discusses the phenomenon in compounds, scientifically
referred to as polymorphism.
Polymorphism comes from the Greek word, Polus = many and
morph = shape. Thus it is defined as the ability of a substance to
exist as two or more crystalline phases that have different ar-
rangements or conformations of the molecules in the crystal
lattice. It essentiallymeans that in different polymorphs, the same
molecule exists in different ways. If this difference is because of
packing, it is termed as packing polymorphism and if it is due to
difference in conformation, it is called conformational polymor-
phism. As a result of polymorphism, molecules have different
arrangements in the unit cell of its crystal and thus display
different physical properties. These include different packing
(left) Rahul Purohit is a
doctoral student in the
Chemistry and Biochem-
istry Department of
University of Arizona
(USA). His research
interests include drug
discovery and biological
chemistry.
(right) P Venugopalan is
a professor in the
Chemistry Department of
Panjab University,
Chandigarh. His
research interests include
crystal engineering, solid
state reactivity, weak
interactions and
polymorphism. He is also
interested in teaching
crystallography.
GENERAL ARTICLE
883 RESONANCE September 2009
properties, thermodynamic properties such as solubility, free energy, melting point, etc.,
spectroscopic properties, kinetic properties such as dissolution rate, stability, and mechanical
properties such as hardness, compatibility, tableting, tensile strength, etc. Polymorphismis very
important in those areas of chemical research where full characterization of a material has a
pivotal role in determining its ultimate use, e.g., in pharmaceutical, pigment, agrochemical,
explosive and fine chemical industries. It is interesting to note that polymorphism has left an
impression even on the history of our world (see Box 1).
The particular advantage of polymorphismis that the chemical identity of the material remains
unchanged from one polymorph to another, so that a direct correlation between activity and
solid state structure may be made. Why does the same chemical, say paracetamol, exist in
different ways in the solid state? The answer is not simple but it is definite that their free energy
difference cannot be huge. In fact, it is just 0.5 to a maximumof about 8 kcal/mol. So some forms
Box 1. Phase Transition in Tin
Polymorphism has a link with Napoleon Bonaparte, the French military and political leader. In the
chilling winter of 1812, the highly decorated and shining buttons on the uniformof Napoleons soldiers
crumbled to dirty grey and the soldiers believed that it is the wrath of God; their morale became so low
that they faced a pathetic defeat at the gates of Moscow.
The scientific reason for the crumbling of the buttons is interesting. At subzero temperatures of
Moscow, the metallic white tin underwent a polymorphic transition to the stable but nonmetallic grey
tin, thus reducing the decorum of the mighty soldiers.
|-Tin or white tin stable above 18
o
C.
Tetragonal, I4
1
/amd
a = b = 5.832, c = 3.182
Metallic
o-Tin or grey tin stable below 18
o
C.
Cubic, Fd3m
a = b = c = 6.489
Non-metallic
Phase
transition
884 RESONANCE September 2009
GENERAL ARTICLE
are slightly unstable compared to others and we can have a functional classification based on
this factor.
Types of Polymorphism
Polymorphs are categorized into two types, monotropes and enantiotropes, depending upon
their stability with respect to the range of temperatures and pressures. If one of the polymorphs
is stable (i.e., has lower free energy content and solubility) over a certain temperature range and
pressure, while the other polymorph is stable over a different temperature range and pressure,
then the two polymorphs are said to be enantiotropes ( Figure 1a). On the other hand, some-
times only one polymorph is stable at all temperatures below the melting point, with all the
other polymorphs being unstable. These polymorphs are said to be monotropes (Figure 1b).
Both types of polymorphs can be easily understood by looking at the graphs. In Figure 1a,
polymorph Ais stable below temperature T
t
(transition temperature), having lesser free energy
G
A
than polymorph B. But as the temperature increases and becomes more than T
t
, free energy
G
B
of polymorph B becomes less than G
A
; thus polymorph B becomes more stable than
polymorph A. This gives rise to an enantiotropic system of solid phases. For an enantiotropic
system, a reversible transition can be observed at a definite transition temperature at which the
Figure 1. Variation of energy with temperature for enantiotropic and monotropic systems. Curves
H
A
, H
B
and H
L
are for enthalpy, whereas H
f,A
and H
f,B
represent enthalpy of fusion and H
t
represents enthalpy of transformation.
Energy
A
B
Liq
M.P. II M.P. I
G
B
H
A
(b) Monotropic system
H
B
H
L
Temp.
G
A
Hf, A
Hf, B
GL
Energy
A
B
Liq
Temp.
T
t
T
f,A
T
f,B
G
A
G
B
H
A
a) Enantiotropic system
H
B
H
L
Hf, B
Hf, A
Ht
GL
885 RESONANCE September 2009
GENERAL ARTICLE
Box 2. Characterization of Polymorphs
Characterization of polymorphs is of utmost importance and there are different analytical methods ranging
fromsimple melting point determination to complete structural determination through single crystal X-ray
crystallography. Other procedures like studying the morphology of crystals by microscopic methods,
observing changes in crystal forms with temperature, phase transition by thermal methods, interpreting
molecular motion and chemical environment by the use of vibrational spectroscopy and solid state NMR
are used depending upon the information sought. Crystallographic methods include both single crystal X-
ray diffraction as well as powder X-ray diffraction. A successful single crystal X-ray diffraction study can
provide unambiguous atomic positions and complete structural information, but obtaining a single crystal
suitable for this study becomes often the bottleneck. In such cases, powder X-ray diffraction studies using
microcrystalline samples become a major tool. In fact, it has become routine to take powder diffractograms
to ascertain the solid state nature and purity of every batch of synthetic drugs.
Another quick and efficient method is to study the crystal morphology by optical microscopy. As unit cell
repetition leads to crystal formation, this feature is reflected in the outer appearance of crystals that can
be observed by simple hand lens or microscope. Further, a detailed study can be performed using
polarizing optical microscopy, electron microscopy and thermal microscopy. The third important method,
which is widely used in pharmaceutical industries for characterization of polymorphism, solvation, purity,
degradation and drug compatibility, is thermal analysis, which includes Thermogravimetry, Differential
Thermal Analysis (DTA) and Differential Scanning Calorimetry (DSC). The study of molecular motions
by use of vibrational spectroscopy is also sometimes employed in the characterization of polymorphs. This
method includes infrared absorption spectroscopy and Raman spectroscopy. Nowadays solid state NMR
is also used for characterization. It studies the chemical environment of the nuclei which is different in
polymorphs because of magnetic non-equivalence. Resonance peaks for the magnetically nonequivalent
nuclei will differ in different polymorphs and can yield very useful information.
free energy curves cross, before the melting point is reached. Whereas in Figure 1b, the
polymorph Ahas its free energy less than the other polymorphs throughout the range belowthe
melting point. For a monotropic system, the free energy curves do not cross, and therefore no
reversible transition can be observed below the melting point; the polymorph with higher free
energy curve and solubility is the unstable polymorph. Generally, it is possible to distinguish
between monotropes and enantiotropes fromtheir heats of fusion. An endothermic polymorphic
transition indicates enantiotropes whereas an exothermic one indicates monotropes. Other than
Differential Scanning Calorimetric (DSC) analysis, there are a number of efficient ways to
characterize polymorphs (see Box 2).
We all knowthat millions of molecules must aggregate to forma crystal. In this process, if there
are energetically viable alternate pathways, molecules may choose anyof these ways depending
886 RESONANCE September 2009
GENERAL ARTICLE
Figure 2. Plot of Gibbs free
energy G of molecular ag-
gregates vs. size of the ag-
gregates. Theredcurverep-
resents total free energy.
The activation free energy
AG* is the free energy at r*.
upon the crystallization conditions This leads to the different polymorphs. Thus formation of a
large enough aggregate (i.e., nucleation) is an important step in the formation of a polymorph.
Nucleation of Polymorphs
Consider the simple case of evaporation of a sugar solution kept in a beaker. As time passes,
more and more molecules of water leave the beaker progressively concentrating the solution
and at a stage (very near to saturation but above it) many sugar molecules come closer to form
aggregates. These will have their characteristic curve of change in Gibbs free energy vs.
aggregate size as shown in Figure 2. The Gibbs free energy difference between the new phase
(that is, the aggregate) and the old phase (that is, the sugar solution) is composed of two terms:
(1) The difference in Gibbs free energy between the two phases in macroscopic quantities
(usually called the volume term, AG
v
), and (2) the difference in Gibbs free energy caused by the
interfacial energy (called the surface term, AG
s
). The total free energy cost, AG
tot
, of forming a
nucleus of a spherical crystal of radius r in a liquid (here sugar solution) is the sumof these two:
AG
tot
=AG
v
+ AG
s
=
3
4
tr
3
A + 4t
2
,
where is the interfacial free energy, is the density of the saturated solution and A is the
chemical potential difference between the newphase and the old phase. The volume term, AG
v
,
varies as r
3
and is negative. The surface term, AG
s
, is always positive and varies as r
2
.
Examination of Figure 2 shows that till a critical size r* is reached, the Gibbs free energychange
increases, and then onwards AG decreases as a result of which an aggregate with r > r* (i.e., a
nucleus) can spontaneously grow. However molecules can also leave the aggregate leading to
complete dissolution of the aggregate (both r and AGdecrease). The surviving aggregates may
not be similar, depending upon how the molecules arrange themselves; they can be of different
Volume
Term
Surface
Term
r*
r
(aggregate radius)
AG*
Gibbs free
energy of
nucleation
AG*
887 RESONANCE September 2009
GENERAL ARTICLE
types, which compete among themselves to grow in size and to give a particular nucleus. The
complete event may be visualized as in Figure 3.
The aggregate present in largest numbers will form the nucleus that grows further to give a
particular polymorph. It is this primary crystallization process involving formation of critical
nuclei which gives rise to polymorphs. This is a general mechanism that explains the usual
situation of crystallization in which polymorphs are crystallized depending upon the conditions
prevailing.
We have learned that who (aggregates) survives succeeds. What are the factors that determine
such a survival? There are many. Molecular conformations, hydrogen bonding, packing
arrangements and lattice energies are a few to cite. But, in forming an aggregate which grows
and to a nucleus then to a specific polymorph, the role of intermolecular interactions is
paramount.
Role of Intermolecular Interactions
The intermolecular interactions like van der Waals interactions, coulombic interactions,
hydrogen bonding, and steric repulsions play an important role in determining the arrangement
of molecules in a crystal. Even the cooperative action of very weak interactions like C-HO
hydrogen bonding, tt, XX (X = halogen), and C-Ht interactions can significantly
contribute towards stabilizing a specific molecular arrangement in a crystal. These weak
interactions are strong enough to cause changes in torsion angles, thereby giving different
conformations and a particular molecular conformation which is near the most stable equilib-
rium conformation is often stabilized. As these interactions are weak and various molecular
conformations can have nearly the same energy, the molecules can crystallize in different
crystal forms.
Molecules capable of possessing torsional degrees of freedom give rise to different conforma-
tions that may be preserved in different crystal forms. The existence of different conformations
Figure 3.
Aggregate 1 Nucleus 1 Polymorph 1
Molecules Aggregate 2 Nucleus 2 Polymorph 2
Aggregate 3 Nucleus 3 Polymorph 3
888 RESONANCE September 2009
GENERAL ARTICLE
of the same molecule in different polymorphic modifications is termed conformational poly-
morphism. Among polymorphic modifications, conformational polymorphs have the major
share. Sometimes polymorphs crystallize simultaneously when conformations are very close
energetically and structurally, and nucleation rates are of the same order of magnitude. If two
or more polymorphs crystallize under identical conditions, then it is known as concomitant
polymorphism.
Although there is a plethora of examples of conformational polymorphism, two of them, which
are shown here, are biologically active compounds. One of the recent examples is Eflucimibe
a new acyl-coenzyme A: Cholesterol O-acyl transferase (ACAT) inhibitor drug. This drug
crystallizes simultaneously intwo polymorphic forms Aand Bwhich differ by a conformational
change of the phenol group in the crystal lattice, that occurs through a rotation of the bond
connecting the amide nitrogen and aromatic ring (Structure 1).
A second example is that of the Vitamin A acid, a member of the family of visual pigments. It
has been reported in two crystalline forms: triclinic and monoclinic.
In Vitamin A acid, the exocyclic bond can acquire two conformations, S-cis and S-trans by
rotation about the bond connecting atoms 1 and 2 (Structure 2). Indeed, it is observed that the
triclinic form exhibits S-cis conformation about the exocyclic bond and has a non-planar
conformation, whereas the monoclinic form is S-trans about the exocyclic bond and is much
more planar in nature.
It is also worth mentioning that so far the number of polymorphs of a given compound has
reached double digits. The maximum of ten
polymorphs for 5-methyl-2-[(2-nitrophenyl)
amino]-3-thiophenecarbonitrile commonly
known as ROY (Figure 4) has been obtained.
The name ROY comes from the Red, Orange
and Yellow color of its polymorphs.
A
HO
N
S
O
H
N
S
O
H
HO
B
Structure 1. Two polymor-
phs of eflucimibe: In Form
A, the OH bearing the aro-
matic ring is in the plane of
the paper, whereas in Form
B it is out of the plane.
COOH
1
2
Structure 2. Vitamin A acid: S-trans isomer.
889 RESONANCE September 2009
GENERAL ARTICLE
In the following we discuss polymorphismexhibited by various inorganic, pharmaceutical and
biological compounds.
Polymorphism in Elements and Inorganic Materials
Polymorphism in the case of elements is termed as Allotropism. The simplest example, as
discussed in the beginning, is that of carbon to which the newentrants are fullerenes and carbon
nanotubes. Other examples include phosphorous (P
4
) in cubic (white), monoclinic (purple) and
orthorhombic (black) forms; Sb in rhombohedral (grey), cubic (grey), hexagonal (metallic)
forms. Boron exists in different allotropes such as tetragonal, rhombohedral, orthorhombic,
monoclinic and hexagonal forms. Alarge number of other elements like actinides and molecular
elements exist in polymorphic forms which interconvert with change of conditions like
temperature and pressure. A typical example is that of uranium:
Uranium (U)orthorhombic (U)tetragonal (941 K) (U)bcc (1047 K).
Polymorphism is also abundant in inorganic minerals that are known by their common names,
Polymorphs of ROY
(1) R P-1
mp 106.2
o
C
u = 21.7
ROY
(6) ORP Pbca
mp 97 C, u = 39.4
(4) OP P2
1
/c
mp 112.7
o
C
u = 46.1
(2) ON P2
1
/c
mp 114.8
o
C
u = 52.6
(5) YN P-1, mp 99 C
u = 104.1
(3) Y P2
1
/c
mp 109.8
o
C
u = 104.7
N
S
H N
O O
C
N
CH3
u
100 m
Y04
R
R
L
(9) YT04 P2
1
/c
mp 106.9
o
C
u = 112.8
(7) RPL
(8) Y04
100
R05
Y04
L
(10) R05
Polymorphs of ROY
(1) R P-1
mp 106.2
o
C
u = 21.7
ROY
(6) ORP Pbca
mp 97 C, u = 39.4
(4) OP P2
1
/c
mp 112.7
o
C
u = 46.1
(2) ON P2
1
/c
mp 114.8
o
C
u = 52.6
(5) YN P-1, mp 99 C
u = 104.1
(3) Y P2
1
/c
mp 109.8
o
C
u = 104.7
N
S
H N
O O
C
N
CH3
u
100 m
Y04
R
R
L
(9) YT04 P2
1
/c
mp 106.9
o
C
u = 112.8
(7) RPL
(8) Y04
100
R05
Y04
L
(10) R05
Figure 4. 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile has been crystallized in ten
polymorphs: Thestructureof themolecule isshowninthefigure. ThesystemhasbeennamedROY
for itsred, orange, andyellowcrystal colors. Thedifferent polymorphsarenamedas, yellowprisms
(Y), redprisms (R), orange needles (ON), orange plates (OP), yellowneedles (YN), orange-redplates
(ORP), and red plates (RPL). The figure is reproduced with permission from the web pages of Prof. Lian Yu of
University of Wisconsin-Madison (see: [Link]
890 RESONANCE September 2009
GENERAL ARTICLE
e.g., ZnS is known in forms referred to as wurtzite and sphalerite; CaCO
3
as calcite, aragonite
and valerite; TiO
2
is known as rutile, brookite and anatase.
Polymorphism in Pharmaceutical Compounds
Most drugs are formulated and marketed in crystalline form. Many of the drug molecules are
highly functionalized and can self-organize in several ways in the solid state with nearly the
same lattice energies. Often solvent may be incorporated in the crystal lattice. These features
and the conformational flexibility of molecules are the primary driving forces for the existence
of crystal polymorphism in active pharmaceutical ingredients (APIs). This makes the study of
polymorphismand crystallization of pharmaceutical compounds highly important. Nowadays,
research on polymorphism and material properties of active drug compounds and excipients
(excipients are ingredients included in a pharmaceutical preparation for the purpose of
improving its physical qualities) is an integral part of drug development. The knowledge of
solid-state properties in an early stage of drug development helps to avoid manufacturing
problems, to fine-tune the performance of drugs and provides space for innovations.
Drugs that were previously known to exist only in a single formare nowshown to have various
polymorphic forms. This has perplexed pharmaceutical companies and now they have to
investigate crystal polymorphism in order to optimize the physical properties of a pharmaceu-
tical solid before the drug development. A large number of pharmaceutical compounds show
polymorphism and books like Polymorphism in Pharmaceutical Compounds [1] are written to
disseminate the knowledge within the scientific community. Some of the important examples
are cited here to show its ubiquity in this area.
Paracetamol, also known as acetaminophen, is the most widely used antipyretic (fever suppres-
sant) and analgesic (pain killer) in the world. Though the drug seems to be simple, it has been
shown to exist in two polymorphic forms. One is monoclinic Form-I (P2
1
/n), which is marketed
whereas Form-II is orthorhombic (Pbca). Similarly, Famotidine which is an excellent histamine
H
2
receptor antagonist is also found to exist in two different polymorphic forms, metastable
polymorph B and stable polymorph A. Piroxicam, a nonsteroidal, anti-inflammatory drug
widely prescribed all over the world exists in three forms I, II and III.
Another important example is Ritonavir. It is a novel protease inhibitor for Human Immunode-
ficiency Virus (HIV), the causative agent of Acquired Immune Deficiency Syndrome (AIDS).
This drug is marketed as Norvir. Launched in 1996 and distributed for about 18 months without
trouble, its manufacturing company Abbott observed an unexpected occurrence. The final
product did not show dissolution and the drug was precipitating. After considerable investiga-
tions it was revealed that this was because of a new thermodynamically more stable and less
891 RESONANCE September 2009
GENERAL ARTICLE
soluble polymorph Form-II. Surprisingly, the companys attempt toformulate Form-I thereafter
turned out very difficult (perhaps the exact conditions could not be reproduced) and put the
company almost into a market crisis. The drug is now often quoted as an example in
pharmaceutical industries to show the importance of polymorphism in this field.
The last example discussed here is of Norfloxacin. It is the widely used synthetic broad-
spectrumantibacterial fluoroquinolone for the treatment of prostate andurinarytract infections.
This drug exists in two anhydrous polymorphs (A and B), an amorphous form and several
hydrated forms. Of the two anhydrous polymorphs, Form B is the most stable at room
temperature. But the commercial sample of norfloxacin used is the FormA, which is metastable
at room temperature.
All these examples clearly show that it is highly important to make the required polymorphic
form, as the other form may not show the desired effects. Usually the form that is most stable
is preferred in market formulation as the metastable form may transformto other stable forms.
But it is a universally accepted rule that the metastable formhas higher solubility than the stable
formand this formconverts into the stable formas a result of spontaneous change but the reverse
never happens. Thus, whenever possible, metastable forms having high solubility that can
survive for years without changing to the stable form are selected for formulation. This means
that, forms that have considerable activation barrier in moving from metastable state to stable
state would be selected. That is, careful evaluation of both thermodynamic parameters (ten-
dency toward formation of more stable polymorphs) and kinetic parameters (which lead to
formation of metastable polymorphs) is of high importance in crystallization process of such
compounds.
Polymorphism of Proteins and Other Biological Compounds
Polymorphism is not confined to the small molecule regime; large molecules like proteins can
also exist in polymorphic forms. Proteins have tertiary and quaternary structures which show
various interactions and because of which they have a particular structure. Proteins can
crystallize in different crystal forms as they can have different conformations of peptide units.
One of the classic examples is lysozyme. It is known to crystallize in six different forms that
differ in water content, nature and amount of anions and difference in packing arrangements. It
exists in triclinic, monoclinic, orthorhombic, trigonal, tetragonal and hexagonal forms. Another
important example is hemoglobin, which is known in monoclinic, orthorhombic and tetragonal
modifications. Many other protein molecules are also known to exist in different forms, like
glutathione-S-transferase from rat liver (three polymorphic forms).
Not only proteins, but its monomer amino acid units also show polymorphism. As these amino
892 RESONANCE September 2009
GENERAL ARTICLE
acid molecules canhave dif-
ferent conformational pref-
erences, they crystallize in
different forms e.g., L-
glutamic acid is known in
two forms, and . Both the
forms are orthorhombic
(P2
1
2
1
2
1
) and crystals have distinct rhombic and needle-like morphologies.
Similarly, DL-methionine crystallizes in two forms, and , which differ in torsion angle about
the biologically important C(4)-S bond. Even the simplest amino acid glycine has three
polymorphs i.e., , and . The thermodynamically stable -form crystallizes in P3
1
, whereas
the less stable -form in P2
1
/n space group and -form appears in P2
1
space group.
From these discussions it is clear that polymorphism has affected many research/commercial
avenues. As this field is growing and expanding, especially in drug and pharmaceutical fields,
legal issues have also cropped up (see Box 3).
Control of Polymorphism
Sometimes an undesired polymorphic form persistently appears, (like the case of Norvir) and
because of this, the commercial form may not be available causing great loss. Therefore, it
becomes necessary to develop methodologies to get the commercially preferable form and
prevent the appearance of the other one. Crystal engineering can provide answers to this
question of control of polymorphism. It is the application of concepts of supramolecular
chemistry to the solid state to engineer the molecules in a desired way. In a crystal, molecules
are held together by a composite interplay of various interactions and understanding themboth
by experiment and theory would also provide the means to control polymorphism. In addition,
by studyingthe polymorphic crystal structures of a compound, various additives can be selected
which mimic the conformation of a given molecule. These additives can be used to control
polymorphismby inhibiting the growth of undesired polymorphic forms, thus crystallizing the
required one. For example, trimesic acid and transglutonic acid, which conformationally mimic
-form of glutamic acid, selectively inhibit the crystallization of the -form and stabilize the
metastable -form of glutamic acid.
While some chemists are finding means to suppress polymorphism, to many others, the search
for newpolymorphs with novel properties is a fascinatingthough arduous task. Either way, new
insights are gathered in this fascinating field and accedes with the view of McCrone who
NH
2
O
HO
O
OH
L-glutamic acid
NH
2
S
O
HO
DL-Methionine
4
Structure 3.
893 RESONANCE September 2009
GENERAL ARTICLE
Box 3. Legal Aspects Associated with Polymorphism
The commercial arena, especially the pharmaceutical
companies, has recently faced many complex legal
issues arising from polymorphism. Most of these is-
sues are concerned with patent cases.
The most famous case is the Zantac patent case, which
is concerned with the solid-state formof Glaxos major
drug, ranitidine hydrochloride, for the treatment of
peptic ulcers. This is a polymorphic drug capable of
adopting two crystal structures. Aprocess resulting in
the crystallization of FormI was patented in 1978; two
years later a more stable crystalline Form II appeared
which was also patented and which subsequently be-
came the active ingredient for Zantac formulations.
When the patent expired in 1995, other generic compa-
nies also came in this field and subsequent legal battles
resulted.
The second case is of Novartis patent case, which was dealt in Madras High Court. This case is about a life-
saving cancer drug Gleevac containing imatinib mesylate. Gleevac offers a cure to the life threatening form
of the cancer chronic myeloid leukemia. Novartis invented imatinib in 1992 and patented it in 1993 in US and
other countries. The company applied for a patent in India in 1998 for |-crystalline formof imatinib mesylate,
which led to a legal scrutiny of Patents Act 1970.
suggested that virtually every compound has different polymorphic forms and that, in general,
the number of forms known for a given compound is proportional to the time and energy spent
in research on that compound.
Suggested Reading
1] H G Brittain (Ed.), Polymorphism in Pharmaceutical Solids, Marcel Dekker, New York, 1999.
[2] J Bernstein, Organic Solid State Chemistry, (Ed. G. R. Desiraju), Elsevier, Amsterdam, pp.471518, 1987.
[3] J Bernstein, R0 J Davey and J O Henck, Angew. Chem. Int. Ed., Vol.38, pp.34403461, 1999.
[4] J D Dunitz and J Bernstein, Acc. Chem. Res., Vol.28, No.4, pp.193200, 1995.
[5] F H Herbstein, Cryst. Growth Des., Vol.4, pp.14191429, 2004.
[6] A Nangia, Acc. Chem. Res., Vol.41, No.5, pp.595604, 2008.
N
O
S
H
N
H
N
N
O
O
HCl
Ranitidine hydorchloride
Imatinib mesylate
N
N
N
H
N
CH
3
HN
O
N
N
CH
3
CH
3
SO
3
H
Address for Correspondence: P Venugopalan, Department of Chemistry, Panjab University, Chandigarh, 160014,
India. Email: venugopalanp@[Link]