884 Current Medicinal Chemistry, 2009, 16, 884-905

Polymorphism and Crystallization of Active Pharmaceutical Ingredients

(APIs)
Jie Lu and Sohrab Rohani*
Department of Chemical and Biochemical Engineering, The University of Western Ontario, London, Ontario, N6A 5B9,
Canada
Abstract: Active pharmaceutical ingredients (APIs), frequently delivered to the patient in the solid-state as part of an ap-
proved dosage form, can exist in such diverse solid forms as polymorphs, pseudopolymorphs, salts, co-crystals and amor-
phous solids. Various solid forms often display different mechanical, thermal, physical and chemical properties that can
remarkably influence the bioavailability, hygroscopicity, stability and other performance characteristics of the drug.
Hence, a thorough understanding of the relationship between the particular solid form of an active pharmaceutical ingre-
dient (API) and its functional properties is important in selecting the most suitable form of the API for development into a
drug product. In past decades, there have been significant efforts on the discovery, selection and control of the solid forms
of APIs and bulk drugs. This contribution discusses the thermodynamics and kinetics of polymorphic systems, the charac-
terization of polymorphs, and the transformation between polymorphs. The major techniques for polymorph discovery and
control developed in the past years are discussed as well.
Keywords: Crystallization, polymorphism, pseudopolymorphism, active pharmaceutical ingredients (APIs), discovery, control.

1. INTRODUCTION and kinetic factors that can affect the polymorph of final
product are discussed. The polymorphic transformation and
Active pharmaceutical ingredients (APIs) are frequently the computational approaches for predicting crystal struc-
delivered to the patient in the solid-state as part of such dos- tures are also included.
age forms as tablets, capsules, granules, powders, etc [1]. No
matter whether as pure drug substances or in formulated 2. SOLID FORMS OF ACTIVE PHARMACEUTICAL
products, APIs can exist in various solid forms, such as INGREDIENTS
polymorphs, pseudopolymorphs (solvates and hydrates),
salts, co-crystals and amorphous solids. Each form may The solid forms in which an API may present include
possess its own unique mechanical, thermal, physical and polymorphs, solvates, hydrates, salts, co-crystals and amor-
chemical properties that can remarkably affect the solubility, phous solids, as shown in Fig. (1). Discovery and identifica-
bioavailability, hygroscopicity, melting point, stability, com- tion of the solid forms of the active pharmaceutical ingredi-
pressibility and other performance characteristics of the drug ent provide various options to develop it into the drug prod-
[2]. Hence, a thorough understanding of the relationship uct. The choice and design of the preferred form should be
between the particular solid form of an API and its func- based on a comparison of the physico-chemical properties, of
tional properties is crucial for selecting the most suitable which the desired properties may lie on the mode of delivery
form of the API for development into a drug product. (e.g., oral, pulmonary, nasal, rectal, transdermal, etc.). There-
Crystallization refers to the formation of solid particles fore the preferred solid form may differ for each optimized
from a vapor, the solidification from a liquid melt or the dosage form [1].
formation of dispersed solids from a solution. Crystalliza-
tion, incorporating wider definition to include precipitation 2.1. Polymorphs
and solid-state transitions, is a major technological process
Polymorphism may be defined as the ability of a com-
for particle formation in pharmaceutical industry [3]. It is
estimated that over 70% of all solid materials are produced pound to exist in two or more crystalline forms in which the
molecules have different arrangements (packing polymor-
by crystallization. As a matter of fact crystallization plays a
phism) and/or conformations (conformational polymor-
key role in defining the physicochemical properties of solid
phism) in the crystal lattice [4,5]. In other words, poly-
APIs and their final dosage forms.
morphs have the same chemical composition, different lat-
An understanding of the solid state leads to a full ac- tice structures and/or different molecular conformations [6-
quirement of the drug properties, which is critical for many 10]. Polymorphism is a widespread phenomenon observed
of the activities of the pharmaceutical industry. In this re- for more than half of all active pharmaceutical ingredients
view, we focus on the polymorphism of active pharmaceuti- [4,11]. So far, only a small quantity of medicinally active
cal ingredients. The identification of polymorphic system substances can be considered for a practical purpose to be
and the characterization of polymorphs are emphasized. The non-polymorphic, e.g., aspirin [12,13]. There still is a theo-
development in polymorph-selective crystallization tech- retical possibility that those non-polymorphic organic com-
nologies has been presented in detail. The thermodynamic pounds may have potential polymorphs [1].
Polymorphs generally have different physical and chemi-
*Address correspondence to this author at the Department of Chemical and cal properties resulting in different stability and bioavailabil-
Biochemical Engineering, The University of Western Ontario, London, ity of drug products [14]. Mebendazole, a kind of broad-
Ontario, N6A 5B9, Canada; Tel: 519-661-4116; Fax: 519-661-3498; spectrum anthelmintic drug against the infestations by as-
E-mail: rohani@[Link]

0929-8673/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 885

Fig. (1). Schematic representation of the structures of solid forms of APIs.

caris, threadworms, hookworms and whipworms, has been Pseudopolymorphs generally show different solubilities,
found to have three polymorphic forms (A, B, C) displaying dissolution rates, mechanical behavior, stability and bio-
solubility and therapeutic differences [15]. The polymorphs availability from their unsolvated counterparts [27]. For
differ with respect to their spectral and thermal properties as example, caffeine hydrate is much less soluble in water than
well. The solubility of the three polymorphs of mebendazole anhydrous caffeine, but the hydrate is much more soluble in
in 0.03M hydrochloric acid is in the order A, C, B. Solubility ethanol than anhydrous caffeine [28]. The monohydrate of
studies and clinical trials have shown that polymorph C is theophylline possesses higher mechanical strength than an-
therapeutically favored [16]. As to the two polymorphs of hydrous theophylline, resulting from a large number of in-
sulfamerazine, Sun and Grant [17] have demonstrated that termolecular hydrogen bonds in its crystal structure [29]. The
polymorph I possesses greater plasticity, compressibility and weaker mechanical strength of the anhydrate makes it more
tabletability than polymorph II. brittle than the monohydrate. Meanwhile, Liu et al. [30] have
further demonstrated that there exist crystallinity differences
One of the most well-known examples of the evolution of
polymorphic APIs into the marketed drug products is Rito- between the anhydrous and hydrated forms of caffeine and
theophylline.
navir (marketed as Norvir® by Abbott Laboratories). Since
the original Norvir® capsule entered into the market, a previ- The propensity of solvents to be included in molecular
ously unknown but thermodynamically more stable poly- crystals closely links with their ability to effectively partici-
morph (form II) of Ritonavir was discovered. This new form pate in hydrogen bonding. Multi-point recognition with
was approximately 50% less soluble in the hydroalcoholic strong and weak hydrogen bonds between solvent and solute
formulation vehicle than form I. Then the original Norvir® molecules can facilitate the retention of organic solvents in
capsule was eventually withdrawn from the market [18], and crystals [20]. During a crystallization process the pre-
a new formulation of Norvir® using form II was launched nucleation solute–solvent aggregates contain solute–solute,
[19]. solute–solvent and solvent–solvent interactions. Strong sol-
ute–solvent interactions shall result in the nucleation of sol-
2.2. Pseudopolymorphs vated crystals [6]. The water molecule, because of its small
size, activity and ability to act as both a hydrogen bond do-
Pseudopolymorphism may be defined as crystalline nor and acceptor, is found to be more capable of linking to
forms of a compound in which solvent molecules are in- drug molecules to form new crystal structures than any other
cluded as an integral part of the structure [20,21]. Pseudo- solvent. Approximately one-third of active pharmaceutical
polymorphs (solvates and hydrates) can be stoichiometric or ingredients can form crystalline hydrates [31]. Based on the
nonstoichiometric in nature [22]. The propensity of an API location of water in their structures, crystalline hydrates can
molecule to form pseudopolymorphs is deemed to be rele- be categorized into three categories [32,33]: (i) isolated lat-
vant to molecular structures, hydrogen bonding ability, and tice site hydrates, e.g. cephadrine dehydrate [34]; (ii) lattice
crystal packing [23-26]. channel hydrates, e.g. theophylline monohydrate [35]; (iii)
886 Current Medicinal Chemistry, 2009 Vol. 16, No. 7 Lu and Rohani

metal-ion coordinated hydrates, e.g. dihydrate and trihydrate cluding 17 polymorphs, 4 solvates, 6 hydrates and the amor-
of disodium adenosine 5
-triphosphate [36]. Owing to the phous solid. Almarsson et al. [48] and Remenar et al. [49]
multiple roles of water, some hydrates can be classified into have applied high-throughput (HT) crystallization technique
more than one category [37]. into the salt screening for sertraline HCl. They have demon-
Solvates and hydrates may be either final or intermediate strated that seemingly minor differences in salt former can
have profound effects on the number of polymorphs and
products of crystallization, and can transform into higher (or
solvates that can be found in the corresponding salts.
lower) solvates or anhydrous “desolvated” forms [3]. Choice
of development of solvated or unsolvated form of an API
shall depend upon its pharmaceutical properties, how long 2.4. Co-Crystals
and under what conditions it can survive [6]. Co-crystals consist of two or more components that are
solid at room temperature. The primary difference between
2.3. Salts co-crystals and salts is that in salts a proton is transferred
During the selection of the most suitable form of the ac- from the acidic to the basic functionality of the crystalliza-
tion partner, or vice versa, whereas in co-crystals no such
tive pharmaceutical ingredient for development into a drug
transfer occurs [50]. On the other hand, the main difference
product, the desirable solid form is generally its thermody-
between co-crystals and solvates is the physical state of the
namically most stable crystalline form [2]. But the stable
separate pure components at room temperature: if one com-
crystal form frequently presents insufficient solubility or
ponent is in liquid state, the crystals are designated as sol-
dissolution rate leading to a poor bioavailability. In this case,
alternative solid forms should be considered. As for those vates; if both components are in solid state, the crystals are
designated as co-crystals [1]. So far co-crystals have been
ionizable compounds, preparing their salt forms by use of
increasingly recognized as an attractive alternative for solid
pharmaceutically acceptable acids or bases is a universal
forms of drug products [51]. Formation of co-crystals using
approach to modulate solubility (or dissolution rate) [38], to
an API with the excipient [52], or with other component
increase chemical stability [39], to improve bioavailability
[53,54], can provide an opportunity to design drug delivery
[40] or to enhance manufacturability [1].
systems at the molecular level and to improve some pharma-
Several strategies for performing the salt selection proc- ceutical properties of the API [6,55].
ess have been developed, such as in-situ salt screening tech-
Co-crystals containing APIs represent a new type of
nique for ranking the solubility of salts [41], the multi-tier
pharmaceutical materials. In addition to potential improve-
approach developed by Morris et al. [42] for the selection of
ments in solubility, bioavailability, and stability, co-crystals
optimal salt form for a new drug candidate. Moreover, the
selection process of pharmaceutical salts can be facilitated may enhance a large number and variety of essential proper-
ties, including hygroscopicity, compressability, and flowabil-
by use of the pKa and pH–solubility curve of the drug [43],
ity [56]. A well-documented case is itraconazole, a poorly
as the type and number of salts that will be formed can thus
water-soluble antifungal drug, which can form co-crystals
be greatly narrowed down [6,38].
with various pharmaceutically acceptable acids, such as
The presence of ions shall greatly influence the physico- fumaric acid, succinic acid and L-, D- or DL-tartaric acid.
chemical properties of the crystals of formed salts, including Different carboxylic acid co-crystals exhibit a higher solubil-
solubility, dissolution rate, hygroscopicity, degree of crystal- ity and a faster dissolution rate than the free itraconazole [5].
linity, crystal habit, and physical and chemical stability The co-crystals of aspirin, rac-ibuprofen and rac-flurbipro-
[44,45]. On the basis of these properties, their suitability for fen have been prepared by disrupting the carboxylic acid
development can be assessed. It is worth noting that, like dimers using 4,4V-bipyridine [57].
their parent compounds, pharmaceutical salts may exist in
several polymorphic, solvated and/or hydrated forms [1]. For Co-crystals can be prepared by melt-crystallization [58],
grinding [59] and recrystallization from solvents [60]. When
example, ranitidine hydrochloride (RAN-HCl) has been
solution crystallization is employed, the co-crystals’ domain
found to have two polymorphic forms and tautomerism is
of existence can be described by the ternary phase diagram
considered as the main reason of structural differences in the
(solvent, molecule, co-crystal former), and the solvent for the
solid state of RAN-HCl [46]. Theoretically, RAN-HCl can
co-crystals must dissolve all components, but must not inter-
have three tautomers (enamine, nitronic acid and imine) in
the solution. Mirmehrabi and Rohani [47] have demonstrated fere with the interactions necessary for co-crystals’ forma-
tion. The screening of co-crystals is thus performed within
that solvents that are strong hydrogen bond donors such as
the given co-crystals’ domain of existence [61]. It is worth
methanol and water interact with nitro group of
noting that co-crystals can also form solvates and exhibit
nitroethenediamine moiety and favor the formation of ni-
polymorphism.
tronic acid tautomer, and nitronic acid is the predominant
tautomer of form 2 crystals. On the other hand, form 1 con-
tains the enamine tautomer, and weak hydrogen bond donor 2.5. Amorphous Solids
solvents or aprotic solvents favor formation of enamine Amorphous solids consist of disordered arrangements of
tautomer and subsequently form 1. molecules and do not possess a distinguishable crystal lattice
Sertraline HCl, the active ingredient in the antidepressant [62]. Amorphous solids lack the three-dimensional long-
Zoloft®, is an example of a salt form that is highly polymor- range order of molecular packing or well-defined molecular
phic and prone to solvate formation. So far 28 forms of ser- conformation if the constituent molecules are conformation-
traline HCl have been disclosed by several companies, in- ally flexible, but may have short-range order [63, 64].
Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 887

Amorphous solid states of an API are far from equilib- GC = H C
T SC (1)
rium than its crystalline counterparts, and possess higher
energy. Amorphous solids normally have desirable pharma- where
H C ,
SC are the enthalpy change and the entropy
ceutical properties such as higher solubility [65], faster dis- change of the crystallization process respectively. From the
solution rate [66], improved bioavailability [67,68] and me-
thermodynamic viewpoint, for a polymorphic system, the
chanical properties [69] compared to their crystalline coun-
terparts. One distinguished example of the applications of minimization of
GC is the classical thermodynamic driver,
amorphous APIs is the formulation of insulin suspensions. which leads to the formation of stable form, whilst the
Various proportions of amorphous, crystalline and com- maximization of the rate of entropy production is the driver
plexed forms of insulin have been marketed to achieve short, in irreversible thermodynamics, which will lead to the for-
intermediate and long acting. However, amorphous solids are mation of less stable form. The equilibrium composition of
less physically and chemically stable than their crystalline the polymorphic mixture will depend on the rate at which
counterparts: (i) very apt to crystallize at a later stage during excess energy is applied to the system [85].
product shelf life [70]; (ii) often reactive and unstable to
mechanical and thermal stresses [71]; and (iii) extraordinar- Meanwhile, the relative thermodynamic stability of
ily sensitive to water sorption [72]. The instability is the polymorphs and the driving force for a transformation at
major reason that amorphous pharmaceutical solids are not constant temperature and pressure is also determined by the
marketed as widely as the crystalline forms [5,6,62]. difference in Gibbs free energy between the polymorphs
Amorphous solids can be prepared by the following
GT and has
processes: (a) rapid precipitation by antisolvent addition
GT = H T
T ST (2)
[73,74]; (b) quenching a melt by rapid cooling [75]; (c)
freeze-drying [76]; (d) spray-drying [77]; (e) fast evaporation where
H T , the enthalpy difference between the poly-
of solvent in liquid solution [78]; (f) introduction of impuri-
ties [79]; (g) milling or grinding crystalline solids at low morphs, reflects the lattice or structural energy differences
temperatures [80]; (h) desolvation of crystalline materials and the entropy difference;
ST , the entropy difference
[81]; and (i) production by solid-dispersion [82]. For exam- between the polymorphs, is related to the disorder and lattice
ple, dehydration of crystalline hydrates has been demon- vibrations. When
GT < 0 , the transformation can occur
strated as a feasible and “gentle” route to the amorphous
state of organic solids [62]. The amorphous form of raffinose spontaneously;
GT = 0 , the free energy of the two phases
and carbamazepine can be produced by the dehydration of is the same;
GT > 0 , the spontaneous transformation is not
their pentahydrate [83] and dihydrate [84], respectively. In
general, production of amorphous solids is compound- possible under the specific conditions.
specific. Relatively large and/or flexible molecules tend to According to the corresponding thermodynamic relation-
form a disordered state even at mild crystallization condi- ships, polymorphs can be classified as either enantiotropes or
tions [3]. monotropes, depending on whether or not one form can
The mechanism of the formation of amorphous solids is transform reversibly to another [86
89]. As for a single-
still not quite clear [3]. Current research in the crystallization component and dimorphic system, three types of Gibbs free
and stabilization of amorphous solids focuses on: (i) the energy versus temperature phase diagram are schematized in
understanding of crystallization kinetics of the amorphous Fig. (2). Fig. (2a) represents a monotropic system, in which
state (amorphous crystallization); (ii) the stabilization of the liquidus line intersects the curves at temperatures lower
labile substances during processing and storage by use of than the thermodynamic equilibration temperature. In other
additives; (iii) the interactions between APIs and excipients; words, one of the forms is always stable below the melting
and (iv) the selection of appropriate storage conditions under points of both forms. As illustrated in Fig. (2a), the free
which amorphous solids are stable [62]. energy of form A is always lower than that of form B at all
temperatures below Tm, A. Consequently, form B can undergo
3. THERMODYNAMICS a spontaneous exothermic transformation to form A at any
temperature. Furthermore, in this case, crystallization of the
As for a polymorphic system, different crystallization two forms is possible, when the rate of the solid-state trans-
operating parameters normally result in different crystalline formation is lower than that of the crystallization.
forms. Hence the control of polymorphic form via crystalli-
zation requires a full understanding of the nucleation, crystal As shown in Fig. (2b) and (2c), the liquidus line inter-
growth, and phase transformation in the crystallization se- sects the curves at temperatures greater than the thermody-
quence. The knowledge about thermodynamic and kinetic namic equilibration temperature, thus the system possesses
properties of the polymorphic system is essential for the the enantiotropic nature. Below Tt, A-B, form A is stable be-
control of polymorphic crystallization. cause the free energy of form A is lower than that of form B,
and form B can undergo spontaneous exothermic transforma-
3.1. Polymorphic Nature and Thermodynamic Stability tion into form A. Above Tt, A-B, form B is the stable solid
phase because its free energy is lower than that of form A,
The Gibbs free energy change
GC of a crystallization and form A can undergo spontaneous endothermic transfor-
process at constant temperature and pressure is mation into form B. It is worth noting that, as shown in Fig.
888 Current Medicinal Chemistry, 2009 Vol. 16, No. 7 Lu and Rohani

Fig. (2). Gibbs free energy curves for dimorphic systems: (a) monotropic; (b) and (c) enantiotropic. Melting points, T m, for the crystalline
phases are shown by the intersection of the curves for the crystalline and liquidus states. Thermodynamic equilibration temperature, Tt,A-B, of
the forms A and B are shown by the intersection of the curves for two crystalline states. Tt,R is the real transition temperature [90].

(2c), the solid-state transformation sometimes is hindered by the Gibbs energy profiles of dimorphic systems can be de-
steric hindrance. In this case, the real transition temperature scribed as Fig. (3) [89].
Tt, R is different from the thermodynamic equilibration tem-
Entropy-of-Fusion Rule
perature (i.e. theoretical transition temperature) Tt, A-B, and
simultaneous occurrence of the two forms during crystalliza- The melting point is defined as the temperature at which
tion is also possible [91]. the liquid is in equilibrium with the solid so that the differ-
ence in Gibbs free energy between the two phases in zero.
3.2. Prediction Rules The entropy of fusion
S f can then be expressed as

As shown in Eq. (2) and Fig. (2), the relative stability of
H f

polymorphs depends on their free energies, such that a more
S f = (3)
stable polymorph has a lower free energy [92,93]. Under a Tf
specific condition, only one polymorph has the lowest free
energy. This polymorph is designated as the thermodynami-
cally stable form and the other polymorphs are termed as
metastable forms. However, the exact course of G isobars
cannot be followed experimentally, since the entropy cannot
be determined. Therefore, a series of rules have been devel-
oped for predicting the relative thermodynamic stability of
polymorphs and the nature of polymorphic system [8,89].
Heat-of-Transition Rule
This rule generalizes that, if an endothermic enthalpy of
phase transition between two crystal forms is observed at a
specific temperature, so then there is a transition point below
this temperature and the two polymorphs are enantiotropi-
cally related. If an exothermic enthalpy of phase transition is
observed at a particular temperature, and there is no transi-
tion at higher temperatures, the two polymorphs may be
monotropically related [86,87].
Heat-of-Fusion Rule
The heat-of-fusion rule indicates that in an enantiotropic
system the higher-melting polymorph of a pair will have the
lower enthalpy of fusion. If the higher-melting polymorph Fig. (3). Schematic diagram for the crystallization progress in a
also has the higher enthalpy of fusion, the two polymorphs dimorphic system from the initial state, G0 , to two different poly-
are monotropically related. The rule will be valid so long as morphs A or B. [6,8].
Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 889

According to the rule, if a polymorph has the higher ing point is always lower than another form with the lower
melting point but has the lower entropy of fusion, the two melting point [89].
polymorphs are enantiotropically related. Monotropism is
inherent if the lower melting polymorph has the lower en- 4. KINETIC CONSIDERATION ON POLYMORPHIC
tropy of fusion [94]. CRYSTALLIZATION
Heat-Capacity Rule
4.1. Nucleation of Polymorphs
At a given temperature, if one polymorph has both the
higher melting point and the higher heat capacity than an- Crystallization is a complicated process of molecular as-
other polymorph, these two polymorphs are enantiotropically sembly with a precise packing arrangement. In the classical
related. For a pair of polymorphs, if the polymorph with the nucleation theory [97], the nucleus is assumed to be spheri-
higher melting point also has a higher heat capacity at a cal, and then the homogeneous nucleation rate is given by
given temperature, there exists an enantiotropic relationship [98]
between them. Otherwise, the system is monotropic [89,92].

Ghom
*
  16 M 2 3 N A 
J = An exp  = An exp
 ln
2 S  (4)
Enthalpy-of-Sublimation Rule RT   3 R T 
3 3 2
 
If the polymorph with the higher melting point has the
lower enthalpy of sublimation, the two polymorphs are enan- where
Ghom
*
is the energy barrier for homogeneous nuclea-
tiotropic. Monotropism is realized if the lower melting form tion, J is the nucleation rate, An is the collision factor,
is
shows the lower enthalpy of fusion [8].
the interfacial energy, S is the supersaturation ratio, N A is
Density Rule the Avogadro's Number.
The most energetically stable structure is expected to cor-
The radius R* of the critical nuclei for homogeneous nu-
respond to the one that has the most efficient packing. The cleation is given by:
two polymorphs are monotropically related if the polymorph
with higher melting point possesses the higher density. Oth- 2
R* = (5)
erwise they are enantiotropically related [8]. This rule is quit
μ
general for ordered molecular solids that are dominated by
van der Waals interactions. Exceptions such as acetazola-
μ  kT ln S (6)
mide [95], are not unexpected when other interactions, such
as hydrogen bonds, dominate the packing, since some ener- where
is the molar volume, k is the Boltzmann's con-
getically favourable hydrogen-bond dominated packing stant.
arrangements can lead to large voids in the crystal structure Heterogeneous nucleation on a surface is generally con-
with correspondingly lower density [86]. sidered to be energetically less demanding than homogene-
Infrared Rule ous nucleation due to lowering of the surface energy of the
nucleus on the substrate upon interfacial contact [99]. Hence
The rule is normally for the hydrogen-bonded crystals.
For the highest frequency infrared absorption band in poly-
Ghet
*
= 
Ghom
*
(7)
morphic structure containing strong hydrogen bonds. The
where
is the ratio of the Gibbs free energy of heterogene-
formation of strong hydrogen bonds is associated with a
reduction in entropy and an increase in the frequency of the ous nucleation to homogeneous nucleation.
vibrational modes of those same hydrogen bonds. The hy- The energy-reaction coordinate diagram of a classical
drogen-bonded polymorphic structure with the higher fre- dimorphic crystallization process can be schematically pre-
quency in the bond stretching modes may be assumed to sented by Fig. (3). Starting from a supersaturated solution of
have the larger entropy [96]. which the free energy per mole of a solute is termed as G0 ,
Solubility Rule form A or B can nucleate. In Fig. (3), form A is more stable
and less soluble than form B. The energy barrier for the
Since the solubility is directly proportional to the free en-
ergy of a polymorph, determination of solubility is the most nucleation of form A ( GA*
G0 ) is greater than that for form
reliable method of assessing
GT between polymorphs. B, ( GB*
G0 ), and the supersaturation with respect to form B
Generally the stable form has a lower solubility. It is impor- (simplified as G0
GB ) is lower than G0
GA for form A.
tant to note that although the absolute solubility of a poly- According to the classical theory of nucleation from homo-
morph will be solvent dependent, the relative solubility of geneous solutions, the size of critical nuclei (critical size) is
different forms will not depend on the solvent used [8].
dependent on the level of supersaturation. The higher the
If one form with a higher melting point has a higher level of supersaturation, the smaller this size is. Based on
solubility at temperatures above the transition temperature, these considerations either form A or form B can nucleate.
polymorphs are enantiotropic. When the polymorphs are When form B is kinetics favorable under specific conditions,
monotropic, the solubility of one form with the higher melt- form B will preferably nucleate and transform to form A.
890 Current Medicinal Chemistry, 2009 Vol. 16, No. 7 Lu and Rohani

The polymorph of final product will depend on both crystal- nate the formation of nuclei and how they are controlled.
lization and transformation rates. From the viewpoint of structure, the polymorph that will
nucleate preferentially from a melt or solution may be the
As to a dimorphic system with the monotropic nature one whose energy barrier is smallest so as to be most easily
(Fig. 4), when a solution equilibrated at A0 is cooled and formed or the one whose structural organization is most
nucleates at A1, only stable form A can nucleate. The poly- readily derived from the molecular arrangement in the melt
morph of metastable form B preferably nucleates when nu- or solution. It is suggested that the metastable form some-
cleation points A2 or A3 are located upper the metastable times appears to have a structure which most closely resem-
limit of polymorph B. If the transformation rate from poly- bles that of the melt or solution [100].
morph B to polymorph A is far lower than the crystallization
rate of polymorph B, e.g. at point A3, pure polymorph B can 4.2. Ostwald Law of Stages and Its Validity
be collected. Otherwise the final product may be the mixture
of both polymorphs. In experimental and industrial practice, it has been com-
monly observed that the metastable form appears first and
then transfer into a more stable structure. From this phe-
nomenon, Ostwald concluded that “when leaving a metasta-
ble state, a given chemical system does not seek out the most
stable state, rather the nearest metastable one that can be
reached without loss of free energy”. That is, in a crystalliza-
tion from the melt or from solution, the solid first formed
will be that which is the least stable of the polymorphs, the
one with the largest Gibbs free energy [101]. Ostwald law of
stages can be explained by that the limit of metastable zone
is closer to the solubility curve for the metastable form than
for the stable form, as shown in the Fig. (4). Besides, the
least stable form normally possesses the highest volume free
energy and the lowest specific step free energy, and thus has
the highest average step velocity and crystal growth rate
[102,103]. As a result, the crystallization of the least stable
form is expected to predominate at high levels of supersatu-
ration. Meanwhile this effect is also dependent upon the
solvent-solute interactions [3].
Fig. (4). Polymorphic system of two monotropically related poly- Although it is a useful indicator of a possible sequence of
morphs A and B. Full lines SA and SB are solubility curves respec- production of crystalline forms, Ostwald law of stages is not
tively; dashed lines SSA and SSB are metastable limits (supersatura- as universal and reliable [4]. This is because the appearance
tion). and evolution of solid forms are determined by the thermo-
Furthermore, it is necessary to take account of the struc- dynamics and the kinetics of nucleation, growth and trans-
tural elements of molecular assembly processes that determi- formation under the specific experimental conditions

Table 1. Analytical Techniques for Characterizing Polymorphs [111]

Category Techniques Information

X-ray diffraction Powder X-ray diffraction Structure, crystallinity, chemical and phase composition, molecular weight, etc.
Single-crystal X-ray diffraction
Vibrational spectroscopy Raman spectroscopy Structure, molecular conformation, chemical and phase composition, hydrogen
bonding, etc.
Infrared spectroscopy
Microscopy Optical microscopy Crystal size and habit, etc.
Scamming electron microscopy
Atomic force microscopy Surface properties, interactions between particles, etc.
Thermal methods Hot-stage Microscopy Melting point, transitions, etc.
Thermogravimetric analysis Melting point, transitions, etc.
Differential thermal analysis Thermal transitions.
Differential scanning calorimetry Melting point, transitions, heat capacity, crystallinity, etc.
Isothermal calorimetry Heat and rate of transition, crystallinity, etc.
Nuclear magnetic resonance Solid-state nuclear magnetic reso- Chemical and phase composition, structure, crystallinity, intermolecular interac-
spectroscopy nance spectroscopy tion, conformational change, etc.
Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 891

[104,105], and by the link between molecular assemblies and assume that polymorphs A and B have characteristic diffrac-
crystal structure [6,106
108]. tion peaks at
A and
B , respectively. The fractions of the
A and B polymorphs in a sample can be calculated from the
5. CHARACTERIZATION OF POLYMORPHS
ratio of the area under their characteristic peaks using the
In the pharmaceutical industry, identification of poly- following equations respectively [113]
morphism during early stage development is critical, as un- peak area of the peak at
A
anticipated polymorphic changes of a drug substance can Fraction of A polymorph =
sum of peak areas of peaks at
A and
B
affect chemical and physical stability, solubility, morphol-
ogy, hygroscopicity, and, ultimately, bioavailability (8)
[109,110]. A number of analytical techniques have been
employed for characterizing polymorphs and in-situ monitor- peak area of the peak at
B
Fraction of B polymorph =
ing the formation and transformation of polymorphs during sum of peak areas of peaks at
A and
B
the process, as listed in Table 1. (9)

5.1. X-Ray Diffraction High quality PXRD data sometimes can be employed to
obtain complete crystal structures and structure determina-
Generally only X-ray crystallographic methods (i.e. X- tion from powder diffraction (SDPD) is currently one of the
ray powder or single-crystal diffraction) can provide defini- exciting frontiers in structural chemistry [114,115]. David et
tive proof of the existence of polymorphism [112]. Single al. [116] determined the crystal structure of capsaicin, thio-
crystal X-ray crystallography is still the most powerful tech- thixene and promazine hydrochloride from their powder
nique for the three-dimensional structure determination for diffraction data.
small molecules and macromolecules as it can provide de-
tailed pictures of the structure of the molecule in the crystal When PXRD is used for the characterization of poly-
lattice. However, high-quality single crystals for X-ray crys- morphs, both differences in particle size and preferred
tallography are sometimes difficult to obtain. On this account orientation [117], together with peaks’ overlap [118], can
powder X-ray diffraction (PXRD) is more popular in the affect the sensitivity of PXRD assays. When samples are
identification of different polymorphs. The positions of the prepared for analysis, the particle size must be closely
peaks in a powder X-ray diffraction pattern correspond to controlled because preferred orientation effects can vary the
periodic spacings of atoms in the solid state; namely, differ- relatively intensity of the diffraction lines. Furthermore,
ent lattice constants will lead to different peak positions (Fig. PXRD does not allow any correlation of individual diffrac-
5). tion peaks with specific structural features. To achieve good
quantitative analysis for polymorphic composition, a
standard curve must be prepared from pure polymorphic
forms, which may or may not be available. Because of these
factors, much research has focused on alternative techniques
for the determination of crystal form [112].

5.2. Infrared Spectroscopy

Vibrational spectroscopic methods for polymorph identi-
fication such as infrared and Raman spectroscopy can pro-
vide information on structure and molecular conformation in
the solid forms by probing vibrations of atoms [6]. Besides,
the subtle spectroscopic changes arising from intermolecular
(hydrogen) bonding can also be observed [119]. Both tech-
niques can be used in estimating polymorphic composition
rapidly and in confirming results obtained from PXRD
analysis.
Infrared spectroscopic techniques are economical and
easily available, and have already been applied to polymorph
characterizations simply by inspection of spectral differences
[112]. Spectroscopic differences have resulted in the identi-
fication of absorbance bands useful for the quantitative
Fig. (5). Powder X-ray diffraction patterns of forms 1 and 2 of analyses of polymorph mixtures. The applied infrared spec-
stavudine crystals. troscopic techniques include diffuse reflectance Fourier
transform infrared (DRIFT-IR) [120], attenuated total reflec-
Furthermore, the generally good separation between tion Fourier transform infrared (ATR-FTIR) [121,122] and
peaks in the diffractogram allows for quantitative analysis of near infrared (NIR) [123]. As shown in Fig. (6), to construct
mixtures of polymorphs using PXRD [2]. For example, let us the calibration curve for quantitative analysis, the character-
892 Current Medicinal Chemistry, 2009 Vol. 16, No. 7 Lu and Rohani

istic peaks at W1 cm
1 and W2 cm
1 are selected for pure A solid state if the compound under study does not exhibit
form and pure B form, respectively. The reference peak at background fluorescence. When Raman spectroscopy is
employed to analyze fluorescent samples, the wavelength of
W0 cm
1, common to both forms, is selected as an internal
the excitation laser can be changed to the near-IR to reduce
standard. The following equation can be employed for cali- fluorescence of problematic samples.
bration [124,125].
At lower frequency vibrational bands, the Raman spec-
trum arises largely due to lattice vibrations that are very
sensitive to structural changes in the solid state. Differences
in the spectral patterns in this region between polymorphs
may also be due to differences in intermolecular interactions
(e.g. hydrogen bonding) and differences in crystal symmetry
in the polymorphs. The bulk of the chemical structure details
can be obtained from the region at higher frequency vibra-
tional bands.
Raman spectroscopy with a microscope can focus on
small crystalline samples. Information about drug dispersal
in the formulated tablet and polymorphic changes occurring
during formulation can thus be analyzed off-line. However,
when spectra are acquired from the surface with a relatively
powerful laser, the surface will be heated which may cause
polymorphic transitions. On the other hand, Raman spectros-
copy has been widely used for in-situ studies of polymor-
phism because it can perform measurements both behind
glass and in solution. For example, by use of in-situ Raman
spectroscopy, Ono et al. [128] conducted in-situ quantitative
Fig. (6). FTIR spectra of the two pure polymorphs and polymorphic measurement of the polymorphic fraction of different poly-
mixture of famotidine [126] illustrating the quantitative analysis of morphs in the batch crystallization process of L-glutamic
polymorphic composition in the mixture. acid. They demonstrated that Raman spectroscopy could be a
a ' bc ' powerful tool for measuring the polymorphic fraction in
Y= (10) suspension.
ab ' c + a ' bc '
where a and a ' are the intensities of the reference peak at 5.4. Microscopy
W0 cm
1 of pure A form and pure B form, respectively. b Microscopy was first applied in the chemical analysis in
and b ' are the intensities of the peak at W1 cm
1 of pure A 1833 by Raspail [129]. In case polymorphs differ in mor-
phology, optical or scanning electron microscopy can be
form and the sample, respectively. c and c ' are the intensi-
used to identify polymorphs or to monitor the crystallization
ties of the peak at W2 of pure B form and the sample. Y is process of a polymorphic system. It is obvious that micros-
the calculation factor. The calibration curve can be obtained copy alone cannot be used to study polymorphism, as there is
by use of plotting the calculation factor Y against the concen- no inherent relationship between the morphology and the
tration of form B in a series of standard samples. The stan- structure of crystals.
dard samples shall be prepared as the mixtures of the two The atomic force microscope (AFM) is a very high-
polymorphs in various mass fractions of form B in the mix- resolution type of scanning probe microscope with
ture. nanometer resolution. Since it was invented by Binnig et al.
Although infrared spectroscopy is quite simple and con- [130] in 1986, AFM has become one of the foremost tools
venient, it is worth noting that the infrared spectra of differ- for imaging the topography of a variety of surfaces at a range
ent polymorphs of some APIs may be almost identical, e.g. of resolutions from the micrometers to the molecular scale
[131] and for direct measurement of discrete intermolecular
the polymorphs I and II of tropine phenylacetate [127]. Be-
forces [132]. An example of applying AFM to polymor-
sides, the difference in infrared spectra may be resulted from
phism is the study conducted by Danesh et al. [133] who
the difference in purity, crystal size and preparation process applied tapping mode atomic force microscopy to distinguish
of the samples. Sample preparation may also introduce and characterize the polymorphs of drug cimetidine. The
changes to the observed absorbance. atomic force microscope was also used to investigate the
interaction forces between individual particles qualitatively
5.3. Raman Spectroscopy as well as quantitatively [134].
Raman spectroscopy provides similar chemical informa-
5.5. Thermogravimetric Analysis
tion to IR spectroscopy [119]. When it is applied to investi-
gate polymorphism, the Raman spectroscopy can be sensi- Thermal analysis includes differential scanning calorime-
tive to polymorphic changes, and thus can be used for the try (DSC), thermal-modulated DSC (TMDSC), differential
quantitative characterization of polymorph transitions in the
Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 893

thermal analysis (DTA), thermogravimetric analysis (TGA), in terms of that various polymorphs have different thermal
hot-stage microscopy (HSM), etc. Thermogravimetric analy- conductivity.
sis (TGA) is an analytical technique used to determine a
material’s thermal stability and its fraction of volatile com- 5.8. Solid-State Nuclear Magnetic Resonance Spectros-
ponents by measuring the weight change that occurs as a copy
sample is heated. The measurement is normally carried out
in air, nitrogen, helium or argon, and the weight is recorded As a nondestructive and noninvasive analytical tech-
as a function of increasing temperature. TGA can thus be nique, solid-state nuclear magnetic resonance (SS-NMR)
used to analyze the processes of decomposition or sublima- spectroscopy can be used to analyze drug formulations, to
tion, and to determine the fraction of solvent in hydrates and study inclusion compounds, and to examine host–guest in-
solvates. teractions [139]. In addition, SS-NMR spectroscopy can be
employed to investigate polymorphism and pseudopolymor-
5.6. Differential Scanning Calorimetry phism by probing the environments of atoms in the solid
state. Non-equivalent nuclei will resonate at different fre-
Differential scanning calorimetry (DSC) measures the quencies and these chemical shift differences may be associ-
amount of energy absorbed (endothermal event) or released ated with changes in conformation or chemical environment
(exothermal event) by a sample either during continuous of the API molecules in different solid forms [6]. That is,
heating/cooling experiments or during isothermal experi- SS-NMR spectroscopy can detect various structures resulting
ments. Such thermodynamic data as melting point, heat ca- from different packings, conformational changes and hydro-
pacity and heat of fusion as well as polymorphic transitions gen bonding. Apart from most often used 13C NMR spec-
can be obtained by use of DSC. When DSC is employed for troscopy, many other nuclei (e.g., 19 F, 15N, 23Na, 31 P, 17O, or
2
the characterization of polymorphs, unknown thermal events H) can be used, depending upon the sample to be studied
such as possible decomposition and recrystallization often [140-142]. As it is quantitative and selective, SS-NMR spec-
occur. Other analytical methods such as PXRD, TGA or troscopy can quantify mixtures of polymorphic crystalline
HSM must be carried out to identify these events. Moreover, forms, or of crystalline and amorphous materials, so that
like other most widely used methods for solid-state charac- polymorphic transformations and molecular motion in the
terization such as PXRD, FTIR spectroscopy and NIR spec- solid can be investigated. All analyses can be performed
troscopy, normal DSC is not sufficiently sensitive for detect- without the need for pure forms or a standard curve [143].
ing relatively low levels (<5%) of polymorphic impurity.
Although it has unique advantages over other analytical
Tong et al. [135] have developed a modified approach to
techniques, SS-NMR spectroscopy has some disadvantages.
quantify trace levels of polymorphic form II impurity in form
For example, it generally demands much expertise in the
I samples of salmeterol xinafoate using a standard DSC
technique to run it properly. Its sensitivity is often insuffi-
instrument.
cient so that a large quantity of sample should be provided to
generate an adequate spectrum when using low natural
5.7. Hot-stage Microscopy abundance nuclei such as 13C. Analysis times of SS-NMR
As a type of thermomicroscopy, hot-stage microscopy experiments may be another problem as they can range from
(HSM) is developed as an analytical technique combing the a few minutes to several days or more, depending upon the
properties of microscopy and thermal analysis to enable the sample and the type of NMR experiment used. Moreover,
characterization of the physicochemical properties of materi- peak assignment in the SS-NMR spectrum sometimes seems
als as a function of temperature. Varying the temperature of a thorny subject because multiple peaks could be present for
a specimen and simultaneous viewing it under a microscope a single nuclear site or the presence of overlapping peaks
can provide plentiful information on melting and/or recrys- [144].
tallization behaviors. Besides, in case polymorphic transi-
tions are accompanied by a change in a crystal’s birefrin- 6. POLYMORPH DISCOVERY AND CONTROL
gence, HSM can be applied for studying the polymorphic
transitions during the processes of heating and cooling. This Various methods have been employed to produce differ-
technique also offers the detection of solvates by observing ent polymorphs of an API, such as cooling or quenching of
the evolution of a gas or liquid from a crystal. Therefore, melts [145], deposition (desublimation) [146], solvent drop
HSM has been widely used for the solid-state characteriza- grinding [147], solution crystallization from single or mixed
tion of bulk drugs, evaluation of crystal forms and hydrates, solvents [148], etc. The crystallization process of poly-
and other physicochemical properties [136]. morphs is consisted of competitive nucleation, growth, and
the transformation from a metastable to a stable form. To
When polymorphs of some APIs (e.g. cimetidine) have selectively crystallize polymorphs, the mechanism of each
close melting points and similar bulk thermal behaviors, elementary step in the crystallization process need be re-
normal thermal methods such as DSC or thermomicroscopy vealed with relation to the operational conditions and the key
cannot be used to identify polymorphs or elucidate the rela- controlling factors. It is recognized that the nucleation proc-
tive stability between polymorphs [137]. Sanders et al. [138] ess is the most important to the control of the polymorphic
have combined scanning thermal microscopy and localized crystallization.
thermal analysis to distinguish the polymorphs of cimetidine
894 Current Medicinal Chemistry, 2009 Vol. 16, No. 7 Lu and Rohani

6.1. Traditional Methods factors, particularly deliberate or adventitious seeds. Obvi-

ously, the effect of temperature has both thermodynamic and
A large number of factors can influence the outcome of kinetic implications, particularly for enantiotropically related
polymorphic crystallization, including supersaturation, tem- polymorphs that change relative stability order near the tran-
perature, solution concentration, cooling rate, solvent, agita- sition temperature [3].
tion, pH, additive, impurity, seeding, interface, etc. Kitamura
[149] has grouped the controlling factors for polymorphic Solvent Screening
crystallization into two groups, where the relative impor- The most active pharmaceutical ingredients are purified
tance of each controlling factor depends on systems and and isolated by crystallization from an appropriate medium
crystallization methods. The primary factors, the basic im- during the final step in the synthetic process. As to the crys-
portant factors in the operation of the polymorphic crystalli- tallization of polymorphic APIs, the discovery of possible
zations, include supersaturation, temperature, seeds, the polymorphs typically starts with crystallization of APIs from
stirring rate, the addition rate of antisolvent, the cooling rate, a number of solvents; the appropriate choice of solvent can
the mixing rate of reactant solutions, etc. On the other hand, have a dramatic effect on the polymorphic outcome of a
such factors as solvents, additives, interfaces, etc. are crystallization process. For example, forms II and III of drug
grouped in the secondary factor group. Both primary and sulfathiazole can be crystallized in water, two other forms I
secondary factor groups impart thermodynamic and kinetic and IV are obtained from acetone, whilst n-propanol gives
effects on polymorphic crystallization. Nevertheless, the only form I [150].
mechanism of the effect and the quantitative relationship
between the operational factors and the crystallization char- Crystallization of polymorphs from solvent may be under
acteristics of polymorphs is not clearly understood yet. kinetic or thermodynamic control depending on the condi-
tions. In the latter case the nature of the solvent will have no
Control of Supersaturation Level relationship with the polymorph produced [105]. Whereas in
According to Eq. 4, the nucleation of polymorphs is de- the former case, the selectivity of solvent upon polymorphs
pendent upon supersaturation level. Fig. (7) schematically is related to kinetic rather than thermodynamic mechanisms,
shows three of possible competitive nucleation types of di- e.g. selective adsorption of solvent molecules on crystal
morphic systems. For example, the nucleation of form A can faces followed by inhibition of nucleation and growth of
be higher than that of form B in whole range of supersatura- particular polymorphic forms [3], the solvent-solute interac-
tion ratio (Fig. 7a), at high supersaturation ratio (Fig. 7b), or tions, etc. [108]. The solution-solute interactions can affect
at both low and high supersaturation ratio (Fig. 7c). For nucleation, crystal growth and solution-mediated polymorph
some polymorphic systems the polymorphs can be selec- transformation [151], which consequently affect the appear-
tively obtained by careful control of the level of supersatura- ance of polymorphs. Besides, such bulk properties of solvent
tion. as viscosity, surface tension, etc. may also affect the crystal-
lization kinetics and the occurrence domain of polymorphs
Control of Nucleation Temperature [97].
The temperature normally affects the intermolecular in- In order to address the effect of solvent on polymor-
teractions, solubility, supersaturation, the collision frequency phism, the ability of hydrogen bonding of solvent is analyzed
between molecules, etc. Therefore, the temperature is one of [152]. Hydrogen bonding can occur between solute–solute,
the predominant operational factors that affect the nuclea- solvent–solvent, and solvent–solute molecules. A solvent
tion, growth and transformation of polymorphs. In the proc- molecule that has greater ability to donate or accept hydro-
ess of crystallization from solution, the effect of crystalliza- gen bonding than the solute molecule will establish hydrogen
tion temperature sometimes may be overshadowed by other

Fig. (7). Schematic illustration of the effect of supersaturation level on the nucleation rates of two polymorphs [8].
Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 895

bonding with the solute molecules and may not allow the tial crystallization. The 5(4'-methylphenyl)-5-methyl-
other solute molecules approach the same site. This will hydantoin is known to crystallize in two polymorphic forms,
affect the final outcome of crystal structure and may even orthorhombic and monoclinic forms. Seeded isothermal
lead to a solvate formation [106]. preferential crystallization method was applied to perform
the separation of the enantiomers at a 2-L scale with two
To a certain extent supercritical fluid can act as a crystal-
types of seeds, monoclinic and orthorhombic. However,
lization medium. Crystallization from the supercritical fluid
orthorhombic form was never obtained in the crops but the
can enhance molecular diffusion and ease of solubility. The
control of temperature, pressure and solvents provides a physical parameters of the crystals produced (size, form,
means to carefully control the occurrence of polymorphs [3]. etc.) were strongly affected by the nature of the polymorph
seeds.
Kordikowski et al. [153] used supercritical CO2 to control
the polymorphs of sulfathiazole. Pure polymorphs of sulfa- Tao et al. [159] seeded the liquid of D-mannitol with its
thiazole were obtained at different temperatures and flow polymorphs (alpha, beta, and delta) and revealed several
rate ratios of CO2/solvent. With methanol forms I, III, and IV cases of cross-nucleation between polymorphs. When seeds
and their mixtures could be crystallized. With acetone form I of the alpha polymorph alone was added, the same poly-
or a mixture of form I and amorphous sulfathiazole was morph grew, whereas at small undercoolings seeds of the
obtained. Moribe et al. [154] found that during the rapid delta polymorph yielded the nucleation of the alpha poly-
expansion of supercritical solutions (RESS) process the morph. The surfaces of metastable anhydrous phases of
stable form of phenylbutazone could transfer to the metasta- theophylline [160] and carbamazepine [161] have been re-
ble form. They [155] recently have contributed a review on ported to facilitate the nucleation of the stable hydrate forms
the application of supercritical carbon dioxide for polymor- during dissolution. In the case of cross-nucleation, the poly-
morphic selectivity of seeding cannot be anticipated.
phic control and for complex formation of APIs.
Introduction of Additives
Seeding Technology
Adding additives sometimes causes a dramatic effect on
Seeding is frequently used to control the product crystal the outcome of crystallization [162]. Through influencing the
polymorph. This control strategy is effectively utilized dur- processes of nucleation and crystal growth, additives often
ing the nucleation phase by adding seeds of the desired form influence the product’s structure, shape, crystal size distribu-
and thus overriding spontaneous nucleation. The effective- tion, purity, bioavailability, stability and shelf life, filterabil-
ness of seeding is greatly related to the amount of solid sur- ity; caking/agglomeration property, etc. Commonly used
faces introduced and crystallization rate. It is expected that additives for the crystallization of small molecules and pro-
more solid surfaces should be introduced when higher crys- teins are listed in Table 2.
tallization rate is conducted.
To date, how additives affect crystallization is still poorly
The drug substance hydroxytriendione exists in three understood. Methods for choosing additives for crystalliza-
modifications, forms I, II and III. The form II, thermody- tion are still largely empirical. Probable mechanisms of the
namically stable form at room temperature, is chosen as the effect of additives on crystallization include: (a) altering
solid-state form for the active pharmaceutical ingredient. solubility and the width of the metastable zone, solution
Spontaneous nucleation will lead to either of the two other structure or thermodynamic phase behavior; (b) varying
forms. Beckmann et al. [156] have developed a seeding adsorbent layer around crystals, but not incorporate into
process to ensure the reproducible crystallization of the de- crystal lattice; (c) being adsorbed on the surface of crystals,
sired form II. Zhou et al. [157] have optimized and con- and blocking growth; (d) incorporating into crystal lattice of
trolled the polymorphic crystallization of etoricoxib by seed- product when additive having similar lattice; (e) changing
ing with the desired polymorph at a moderate supersaturation surface energy of the crystals, etc.
condition. As for the polymorphic crystallization of chiral If a compound, which is similar in character to the form-
compound, Courvoisier et al. [158] have investigated the ing nuclei, is attached to a surface, the crystal growth rate
effect of the polymorphic form of the seeds on the preferen- may be altered. In solution, structurally similar additives

Table 2. Additives Frequently Used in the Crystallization Process

Crystallization of proteins Crystallization of small molecules

+ + 2+ 2+ 2+ 2+ 2+ 3+ 3+ 3+ + 2+ 2+
Metal ions: Co , Cs , Ca , Mg , Mn , Zn , Cd , etc, Metal ions: Cr , Fe , Al , Cu , Cd , Mn , etc,
from 0.05M ~ 0.1M from ppm ~ large quantity
Surfactants: non-ionic and ionic surfactants, Surfactants: sodium dodecyl benzenesulfonate (SDBS),
non-ionic detergents surfactant gels, etc.
Organic compounds: dimethyl sulfoxide (DMSO), urea, Salts: sodium chloride, ammonium chloride, etc.
glycine, alditols, phenol, diols, glycerol, Organic compounds: urea, oxalate, alcohols,
polyethylene glycols (PEGs), amino acids, etc.
polysaccharides, etc.
896 Current Medicinal Chemistry, 2009 Vol. 16, No. 7 Lu and Rohani

may influence crystal structure by selectively binding the rived using well-known concepts coupling the ideas of pre-
faces of a growing crystal. When the crystal structures of cipitation and diffusion mass transport in a restricted geome-
polymorphs are already known then the design of the pro- try [168], where high supersaturation can be produced and,
moters or inhibitors for nucleation or crystal growth is feasi- turbulence and convection are reduced. Recently capillary
ble by use of tailor-made additives [6]. Flufenamic acid crystallization techniques have been applied for polymorph
(FFA) is a kind of nonsteroidal anti-inflammatory drug. Its generation. For example, Chyall et al. [169] obtained a me-
metastable polymorph V can undergo a rapid interface- tastable polymorph of nabumetone (4-(6-methoxy-2-
mediated polymorphic transformation. Lee et al. [163] used naphthalenyl)-2-butanone), by evaporation of a 1:3 water-
a salt additive ammonium chloride to induce crystallization acetone solution at room temperature inside a 1.0 mm capil-
of the metastable polymorph V of FFA. In addition, reaction lary tube. In addition to providing high levels of supersatura-
byproducts and other impurities sometimes can influence the tion the evaporation of a solution in a capillary is nonturbu-
polymorphic outcome and crystal properties [1]. 4-Methyl-2- lent and convection is minimized, which provides quiescent
nitroacetanilide has three polymorphs; He et al. [164] have growth environments and may promote the generation of
investigated the effects of the isomorphic molecules 4- crystal forms not easily attainable using other methods. The
chloro-2-nitroacetanilide and 2-nitro-4-trifluoromethyl- metastable polymorph (form B) of metformin hydrochloride
acetanilide on the crystallization of 4-Methyl-2-nitro- was also obtained by capillary crystallization [170].
acetanilide. At the same doping level the percentage of 4-
chloro-2-nitroacetanilide incorporated into the crystal lattice Apart from the preparation of new polymorphs of organic
of polymorph A is much higher than that of 2-nitro-4- compounds, a particular advantage of capillary crystalliza-
trifluoromethyl acetanilide. Mirmehrabi and Rohani [165] tion is that the produced crystals can be directly analyzed by
found that the impurities thymine and thymidine had signifi- PXRD or single crystal X-ray diffraction without removal
cant effects on the crystal habit and crystal bulk density of from the crystallization vessel [6].
stavudine but had no influence on the polymorphic structure. Nucleation Confined in Nanopores
Polymer-Induced Heteronucleation The unique characteristics of nucleation suggest that nu-
When the surface introduced can decrease the free energy cleation in specific pores possessing dimensions near the size
for nucleation, heterogeneous nucleation occurs much faster. of critical nuclei typically in nanometer scale can be regu-
One kind of approach to controlling polymorphism that di- lated through adjustment of the pore size. This adjustment
rectly targets nucleation is the method of polymer-induced may provide a possibility that polymorphs can selectively
heteronucleation. In this method APIs are crystallized in the nucleate in these pores, as polymorphs may have different
presence of polymeric nucleants that mimic the pharmaceuti- critical nuclei sizes. Recently, Ha et al. [171] reported a
cals by solvent evaporation, cooling, sublimation or other novel approach to polymorph selectivity under nanoscopic
traditional crystallization techniques. Crystallization in the confinement. They found that, the form III of anthranilic acid
presence of polymer heteronuclei controls formation of dif- crystallized in the pores of 55-nm CPG (controlled pore
ferent polymorphs presumably through a selective nucleation glass), whereas the form II became evident in 23-nm CPG
process mediated by the polymer surface. The first applica- and was clearly predominant in 7.5-nm CPG.
tion of polymer heteronuclei for crystalline polymorph selec- Heteronucleation on Substrates
tion was conducted by Lang et al. [166]. In their work, the
presence of certain polymers including nylons, isotactic A variety of substrates have long been employed in con-
polypropylene, chlorinated polyethylene, poly(tetrafluor- trolling polymorphism in crystallization process. Selective
oethylene), poly(2,3,5-tribromostyrene), and poly(vinyl growth of a thermodynamically less preferred polymorph of
chloride) was found to cause the growth of the orthorhombic the salt (DMTC+)(TMO
)·CHCl3 has been achieved from
polymorph of acetaminophen from evaporation of aqueous CHCl3 solutions by nucleation on single-crystal succinic acid
solution. Whereas, other polymers such as ethyl cellulose, substrates [99]. This can be explained by a ledge-directed
polycarbonate, poly(vinyl acetate), etc. favored the mono- epitaxy mechanism in which the dihedral angle between two
clinic form of acetaminophen. The orientation of crystal close-packed planes of a substrate ledge site matches that of
growth from the polymer surface varied between polymer two close-packed planes of a prenucleation aggregate corre-
types, indicating an important role for stabilization of the sponding to the observed polymorph. By extending this
crystal faces by the polymers through specific interactions. method, a combinatorial library of inorganic and organic
crystal surfaces has been used as substrates for the poly-
This technique has also been applied for other polymor- morph discovery of many compounds by the epitaxial
phic systems, such as carbamazepine, sulfamethoxazole and mechanism [172]. Another impressive example on this sub-
5-methyl-2-[(2-nitrophenyl)amino]-3-thiophene carbonitrile ject is that selective nucleation and discovery of polymorphs
(ROY) [167]. Briefly, the polymer can act as an additional of ROY were accomplished through the epitaxial growth on
diversity element to affect the crystallization outcome. single-crystal substrates. ROY has six structurally character-
Polymer-induced heteronucleation is expected to control the ized conformational polymorphs. The yellow needle poly-
formation of established forms and to discover unknown morph of ROY can be collected through the sublimation of
polymorphs without prior knowledge of solid-state structure ROY on the (101) face of a pimelic acid single crystal.
[6]. Whereas the sublimation of ROY on the (010) face of a
Capillary Crystallization succinic acid single crystal resulted in the concomitant for-
mation of three polymorphs: yellow needles, orange needles,
Counterdiffusion crystallization in capillary primarily di- and red plates. The red plates were designated as the seventh
rected toward protein crystallization. Its principles are de- form of ROY [173].
Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 897

An alternative strategy for polymorph control by use of a large variety of parameters of composition and process
surfaces is to introduce self-assembled monolayers (SAMs) conditions are investigated in parallel. The API can be dis-
into the crystallization solution which can selectively pro- pensed in the solid state with appropriate powder-handling
mote or inhibit the heterogeneous nucleation of a specific systems, or as a solution followed by solvent removal. Then
polymorph. Hiremath et al. [174] have demonstrated that combinations of solvents and/or additives are added to each
functionalized SAMs can be used as substrates for the selec- crystallization vessel. Liquid transfers can be achieved using
tive growth of a less stable polymorph of 2-iodo-4- liquid-handling robots or multi-channel pipettors. The most
nitroaniline. Orthorhombic and triclinic crystals of 2-iodo-4- used crystallization methods include cooling crystallization,
nitroaniline grow concomitantly from supersaturated ethanol antisolvent crystallization, evaporative crystallization, pre-
solutions, but the less stable orthorhombic form can be selec- cipitation, etc. Crystals produced in the vessels are analyzed
tively grown on 3’-X-4-mercaptobiphenyl (X=NO2, I) self- by a combination of optical image analysis, Raman spectros-
assembled monolayer templates. copy and/or PXRD to differentiate polymorphs. Because the
number of crystallization trials under different experimental
Laser-Induced Nucleation
conditions is greatly increased by an HT approach, the prob-
External fields such as ultrasonic field, electric field and ability of discovering new forms is increased. After a par-
magnetic filed have been attempted to influence the crystal- ticular form at small scale is identified in the HT screening,
lization process of small molecules and proteins. However, scale-up studies will be conducted to further optimize the
the mechanism of accelerating or suppressing nucleation by process for laboratory scale production [1,6].
these fields is still ambiguous.
The HT crystallization has been applied to discover solid
Nonphotochemical, laser-induced nucleation (NPLIN) forms for a series of APIs, such as acetaminophen, sulfathia-
has been suggested as a crystallization technique that can zole, etc. Peterson et al. [177] discovered the highly unstable
effectively affect nucleation process and thus the outcome of form III of acetaminophen by use of the HT crystallization
crystallization. Garetz et al. [175] firstly reported an experi- technique. Another example is that solid forms of the salts of
ment in which nucleation of supersaturated solutions of urea sulfathiazole were explored through HT crystallization tech-
in water might be induced when exposed to intense, plane- nique by use of varying stoichiometric ratios of pharmaceu-
polarized pulses of near-infrared laser light. A photochemi- tically acceptable organic and mineral bases [178]. The
cal mechanism for the process has been proposed, i.e., the screen resulted in the rapid identification and characteriza-
electric field may induce the alignment of urea molecules in tion of 10 salt forms and showed that the salts exhibited a
preexisting clusters of randomly oriented urea molecules, range of melting points depending on the counter-ion type
which can help them to organize to form a crystallite. In and stoichiometric ratio. Briefly, HT crystallization technol-
other investigations by the same group, it was demonstrated ogy can provide rapid and comprehensive discovery of solid
that the technique could provide polymorphic selectivity. forms of APIs, which thus can facilitate selecting the optimal
When supersaturated aqueous solutions of glycine exposed physical or chemical form of a given API for development
to intense pulses of plane-polarized laser light at 1.06
m, into a drug product.
the least stable  form of glycine unexpectedly crystallized.
Crystal Structure Prediction
Whereas the most stable
form was always produced when
the same solutions was not exposed to the laser. This result The ultimate goal of crystal structure prediction is to pre-
suggests that NPLIN may be a promising approach to poly- dict the crystal structure from the molecular structure of a
morph control and discovery [176]. compound. Although various research groups have success-
fully predicted the structures of some small, relatively rigid
6.2. New Approaches organic molecules with few functional groups in last dec-
ades, it remains troublesome to predict the crystal structure
Recent advances in computational chemistry, combina- of a compound from its chemical composition [179]. To
tional technologies, experimental techniques, hardware and date, it is still extremely difficult to predict the influence of
software systems have triggered some new approaches to the subtle conformational changes and weak interactions be-
solid forms’ discovery for APIs, such as high-throughput tween adjacent molecules on the crystalline structure [1].
crystallization, crystal structure prediction, etc. Even if a crystalline form can be predicted, its relative stabil-
High-Throughput Crystallization ity to other crystalline forms is difficult to predict with accu-
racy. In addition, the crystal structure prediction for either
To explore an API’s polymorphs, hydrates, solvates, multi-component (e.g., solvates, hydrates, co-crystals) or
salts, co-crystals and amorphous states, a huge number of ionic systems is not yet possible [180,181].
experimental conditions should be carried out, which is quite
difficult and time-consuming by conventional experimental The theory of Kitaigorodsky is typically employed for
methods. As the concepts of high-throughput (HT) screening the crystal structure prediction [182]. Interactions between
and combinatorial synthesis are applied to the development molecules are assumed to be weak and lacking in directional-
of drugs, high-throughput (HT) crystallization systems have ity. In addition, it is assumed that all interactions taper off at
recently been developed and are emerging as an accelerator longer distances in roughly the same way. In such an iso-
for the discovery and screening of solid forms of an API tropic model, close packing dominates the formation of crys-
[177]. tal structures, thus hypothetical crystal structures that ap-
In a fully integrated HT system, crystallization is per- proximately satisfy these close-packing conditions can be
formed at small scale using a combinatorial approach, where generated by computer programs. Among these calculated
898 Current Medicinal Chemistry, 2009 Vol. 16, No. 7 Lu and Rohani

Table 3. Examples of Polymorphic Active Pharmaceutical Ingredients in the Literature

Compound Forms Crystallization methods Factors investigated Refs.

Abecarnil A, B, C  Cooling  Supersaturation  Impurity [186]

 Supercritical antisolvent  Temperature  Solvent
Acetaminophen I, II, III, trihy-  Cooling  Polymer heteronuclei [167]
drate  Evaporation  Excipient [187]
p-Aminobenzoic acid
,   Cooling  Solvent  Cooling rate [188]
Carbamazepine
, , , 2 sol-  Solution-mediated  Surfactant [161]
vates transformation
Cimetidine A, B, C, D,  Evaporation  Solvent [137]
monohydrate  Cooling  Cooling rate
Diflunisal I, II, III, IV, 2  Crystal structure  Hydrogen-bonding [185]
solvates prediction
Eflucimibe A, B  Cooling  Cooling rate  Seeding [189]
 Initial concentration
Estradiol A, B, 2 sol-  Evaporation  Solid-state characterization [190]
vates  Melt
Ethylenediammonium Monoclinic,  Reactive  pH [191]
3,5-dinitrobenzoate Triclinic
Famotidine A, B  Cooling  Solvent  Temperature [126]
 Cooling rate  Seeding
 Initial concentration
Fluconazole I, II  Supercritical antisolvent  Solvent [192]
Fluticasone propion- 1, 2  Supercritical antisolvent  Structure determination through [193]
ate powder X-ray diffraction
(R,R)-Formoterol A, B, C  Reactive  Impurity [194]
tartrate
L-glutamic acid
,   Cooling  Amino acid additive [195]
Hydroxytriendione I, II, III  Cooling  Seeding [156]
 Evaporation  Solvent
Indomethacin
, ,   Cooling  Substrate [196]
Mebendazole A, B, C  Cooling  Solid-state characterization [16]
Metformin hydrochlo- A, B  Capillary  Solvent [170]
ride
Nabumetone I, II  Evaporation  Solid-state characterization [197]
Nifedipine I, II, III, 5  Evaporation  Solid-state characterization [198]
solvates
Oxybuprocaine hy- I, II, III  Molecular modeling.  Hydrogen-bonding [199]
drochloride

Phenylbutazone
, , , ,   Cooling  Supersaturation [113]

Progesterone 1, 2  Crystal structure  Solvent [200]
prediction  Hydrogen-bonding
Ranitidine hydrochlo- 1, 2  Antisolvent  Solvent [47]
ride
Ribavirin I, II  Cooling  Solid-state characterization [135]
 Melt
Ritonavir I, II  Evaporation  Solvent [201]
 Solution-mediated transformation [202]
 High-throughput
Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 899

(Table 3). Contd…..

Compound Forms Crystallization methods Factors investigated Refs.

Salmeterol xinafoate I, II
Supercritical antisolvent
Temperature
Pressure [203]

Sertraline hydrochlo- 28
High-throughput
Solvent [49]
ride
Salt former
Stavudine I, II, 1 hydrate
Cooling
Solvent
Agitation [165]

Supersaturation
Impurity
Stearic acid A, B, C, D, E
Cooling
Solvent [204]
Sulfamerazine I, II
Solution-mediated
Solvent [108]
transformation
Additive (impurity) [205]
Sulfamethoxazole I, II, III, IV
Evaporation
Polymer heteronuclei [167]

Solvent
Sulfathiazole I, II, III, IV, V
Cooling
Solvent [206]

Evaporation
Template [207]

SEDS
Supercritical CO2 [153]
Sulindac I, II, III, 3
Cooling
Solvent [208]
solvates
Thiazole derivative, A, B, C, 2
Antisolvent
Solvent
Addition rate [149]
BPT solvates
Initial concentration
Tolbutamide I, II, III, IV
Cooling
Additive (cyclodextrin) [209]

Supercritical antisolvent
Additive (metal ion) [210]

Solvent [211]
Venlafaxine hydro- 1, 2, 3, 4, 5, 6
Solid-to-solid
Temperature [212]
chloride transformation

structures some may not be observed in experimental studies. of polymorphic forms, are not well understood [106]. As a
For example, approximately half of the energetically feasible result, the prediction for assessing polymorphic behavior of
predicted crystal structures of carbamazepine exhibit the active pharmaceutical ingredients remains a great challenge.
C=OH
N R 22 (8) dimer motif, and have been observed in It is expected that the on-going development of theoretical
methods coupled with validation of the predictions through
the known polymorphs. Whereas the other energetically extensive crystallization screening will bring about better
feasible structures with the C=OH
N C(4) chain hydrogen models and computational methods [1].
bond motif have not been observed yet. This is attributed to
In summary, multifarious techniques have been devel-
that the kinetics favored the nucleation of crystal structures oped for the discovery and control of the polymorphs of
based on the R 22 (8) dimer motif [183]. Recently some re- active pharmaceutical ingredients. A list of examples of
search groups have incorporated the kinetic factor during polymorphic systems that have been systematically studied is
crystallization into the overall prediction process [5,184]. presented in Table 3. Nevertheless, among those existing
techniques there is still no method to guarantee the produc-
Crystal structure prediction is beneficial to solid form tion of desired form even the most thermodynamically stable
discovery for active pharmaceutical ingredients. Some hy- form of an API [6]. There remains a lack of fundamental
drogen-bonding motifs or molecular layer types are fre- understanding of the nucleation process and those factors
quently observed in the predicted structures, which can be that may contribute to crystallization of diverse forms of a
used to assist the design of crystallization experiments. Cross compound. In the cause of polymorph discovery and control,
et al. [185] combined crystal structure prediction with tar- the mechanisms of the effects of crystallization conditions on
geted experimental crystallization to screen the solid forms the nucleation, crystal growth and transformation of poly-
of diflunisal. Graph set analysis was used to analyze and morphs needs to be further clarified.
classify the structural predictions, and crystallization sol-
vents were selected to promote the formation of crystals 7. POLYMORPHIC TRANSFORMATION
containing the most commonly predicted hydrogen-bonding
motifs. Four new crystal structures of diflunisal were dis- When an API exhibits polymorphism, the knowledge of
covered, including two solvates and two new polymorphs. the relative stability and the transformation kinetics between
In spite of more than a century of great efforts, the fun- polymorphs is essential to the development of its drug prod-
damental mechanisms and molecular properties that drive uct and to the appropriate storage condition. Many pharma-
molecular crystal form diversity, specifically the nucleation ceutical crystals, such as theophylline [213], chlorpropamide
[214], carbamazepine [215], etc., are known to undergo a
900 Current Medicinal Chemistry, 2009 Vol. 16, No. 7 Lu and Rohani

variety of polymorphic transformations during their process- Because of its tremendous advantages over other tech-
ing and formulation. These polymorphic transformations niques, in-situ Raman spectroscopy has recently been widely
shall affect the stability and the bioavailability of drug prod- used to monitor the solution-mediated polymorphic trans-
ucts. formation. By use of Raman spectroscopy coupled with an
Polymorphic transformations proceed generally via the immersible fiber optic probe, Wang et al. [219] have studied
the solution-mediated polymorphic transformation from form
solid-solid or the solution-mediated mechanism [209]. The
II to form I of progesterone.
kinetics of polymorphic transformation of drugs can be af-
fected by such variables as the structure of the product, im-
perfections within the crystal structure and sample history 8. SUMMARY
[215]. The process of polymorphic transformation can be
monitored by in-situ or off-line analytical techniques. In the last decades, great progress has been made in the
understanding of the mechanisms of polymorphism, which
7.1. Solid-Solid Transformation leads to the molecular level design of pharmaceutical solids
and better control of the desired forms. Polymorph control
The solid-solid transformation is dependent on internal has advanced from being a mysterious process to a meaning-
rearrangements or conformational changes of the molecules ful tool to solve the problems occurring in the process of
in crystals [209]. Stress-induced transformation refers to that drug development. It is recognized that the interplay between
solid-solid transformations of APIs are caused by mechanical molecular structures, intermolecular interactions, thermody-
stress. This kind of phase transformation is more frequently namics, and kinetics may affect the processes of molecular
associated with the formation of metastable forms or amor- assemblies and thus can determine the crystallization out-
phous states [6]. Betamethasone acetate has three polymor- comes. This review has introduced the mechanisms of poly-
phic forms (form II, I
, I) and a hydrate. When the three morphism and recent advances in the technologies for the
polymorphic forms were subjected to the ball-milling in an characterization, discovery and control of polymorphs. It is
agate centrifugal mill, the crystallinity of all three forms expected that new crystal forms with novel properties and for
decreased with time during the grinding and gradually turned novel drug products will explosively expand with the pro-
to the amorphous state [216]. gresses in high-throughput crystallization and crystal struc-
ture prediction techniques.
Temperature-induced transformation is another wide-
spread phenomenon of solid-solid transformation. The form
II of betamethasone acetate was completely converted to the ABBREVIATIONS
form I when heated at 160 °C for 15 min. The form I
at 95
°C for 7 days transformed to the form I partially, but the AFM = Atomic force microscope
same treatment did not cause any change of the form I API = Active pharmaceutical ingredient
[216]. By use of terahertz pulsed spectroscopy and differen-
tial scanning calorimetry, Zeitler et al. [217] found forms III, ATR-FTIR = Attenuated total reflection Fourier trans-
IV, and V of sulfathiazole converted to form I via a solid– form infrared
solid phase transition at temperatures below 450 K. CPG = Controlled pore glass
DRIFT-IR = Diffuse reflectance Fourier transform infra-
7.2. Solution-Mediated Transformation
red
The solution-mediated transformation is controlled by DSC = Differential scanning calorimetry
differences in solubility of stable and metastable forms,
where a metastable form possesses higher solubility [209]. If DTA = Differential thermal analysis
the starting point lies within the metastable zone of the stable FFA = Flufenamic acid
phase, the transformation starts only after elapse of the cor-
responding induction period. In the case when the starting HSM = Hot-stage microscopy
point is located outside the metastable zone of the stable HT = High-throughput
solute, the transformation proceeds without any delay [218].
NIR = Near infrared
When the temperature is increased and/or the stable form is
introduced as “seed”, the transformation process normally NPLIN = Nonphotochemical, laser-induced nuclea-
shall be accelerated. tion
Skrdla et al. [112] have systematically investigated the PXRD = Powder X-ray diffraction
solution-mediated transformation of a pharmaceutical com-
RAN-HCl = Ranitidine hydrochloride
pound (2R,3S)-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]
ethyl}oxy)-3-(4-fluorophenyl) morpholine hydrochloride RESS = Rapid expansion of supercritical solutions
from metastable form II to stable form I, by use of FTIR. ROY = 5-methyl-2-[(2-nitrophenyl)amino]-3-
The time-course of transformation is found to be in accor- thiophene carbonitrile
dance with the Prout-Tompkins model. Based on the Ar-
rhenius plot consisting of the natural logarithm of the reac- SAM = Self-assembled monolayer
tion rate constants plotted against their corresponding recip- SDPD = Structure determination from powder dif-
rocal temperatures, the energy of activation for the transfor- fraction
mation from form II to form I is obtained as 42 kJ/mol.
Polymorphism and Crystallization of Active Pharmaceutical Current Medicinal Chemistry, 2009 Vol. 16, No. 7 901

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TGA = Thermogravimetric analysis zole. Chem. Commun., 2001, 603-4.
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TMDSC = Thermal-modulated DSC crystals. Cryst. Eng. Commun., 2002, 4, 454-61.
[26] Gillon, A.L.; Feeder, N.; Davey, R.J.; Storey, R. Hydration in
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Received: November 26, 2008 Revised: January 30, 2009 Accepted: January 30, 2009