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Crystal Polymorphism in Pharmaceutical Science
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DOI: 10.1016/B978-0-12-409547-2.12570-3
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From Thakuria, R.; Thakur, T. S. (2017) Crystal Polymorphism in Pharmaceutical Science.

In: Atwood, J. L., (ed.) Comprehensive Supramolecular Chemistry II, vol. 5, pp.
283–309. Oxford: Elsevier.
ISBN: 9780128031988
Copyright © 2017 Elsevier Ltd. All rights reserved.
Elsevier
5.13 Crystal Polymorphism in Pharmaceutical Science

R Thakuria, Gauhati University, Guwahati, India
TS Thakur, CSIR-Central Drug Research Institute, Lucknow, India
Ó 2017 Elsevier Ltd. All rights reserved.
5.13.1 Introduction 283

5.13.1.1 Polymorphism and Its Impact on Pharmaceutical Solid Form Selection 283
5.13.1.2 Definition and General Classification/Types 284
5.13.1.3 Pseudopolymorphism and Polymorphism in Other Multicomponent Systems 285
5.13.1.4 Ostwald’s Rule of Stages, Concomitancy, Intergrowth, and High Z 0 Polymorphs 286
5.13.2 Experimental Approaches for Polymorph Screening and Characterization 286
5.13.2.1 Polymorph Screening Methods 286
5.13.2.2 Characterization of Polymorphic Forms 289
5.13.2.2.1 X-ray diffraction 289
5.13.2.2.2 Thermal methods 289
5.13.2.2.3 Spectroscopic methods 290
5.13.2.2.4 AFM, nanoindentation, and TEM methods 292
5.13.3 Impact of Polymorphism on the Physicochemical Properties of Drugs 293
5.13.3.1 Solubility 293
5.13.3.2 Dissolution Rate and Bioavailability 293
5.13.3.3 Hygroscopicity 295
5.13.3.4 Chemical Stability 298
5.13.3.5 Mechanical Properties 299
5.13.4 Computational Methods of Polymorph Prediction and Characterization 300
5.13.4.1 CSP and CCDC Blind Tests 300
5.13.4.2 Many-Body Dispersion Approaches 301
5.13.4.3 Crystal Structure and Energy Landscape 302
5.13.5 Regulatory and Patentability Aspects of Drug Polymorphs 302
5.13.5.1 Drug Polymorphs and Regulatory Approval of Generic Variants 302
5.13.5.2 Ranitidine Hydrochloride (Glaxo vs Novopharm) 303
5.13.5.3 Paroxetine Hydrochloride (SmithKline Beecham vs Apotex) 303
5.13.5.4 Amlodipine (Pfizer vs Apotex) 304
5.13.5.5 Imatinib Mesylate (Novartis vs Government of India) 304
References 305
5.13.1 Introduction
5.13.1.1 Polymorphism and Its Impact on Pharmaceutical Solid Form Selection
Drugs are preferably administered as solids due to the ease of handling, better manufacturability characteristics, and their higher
chemical and physical stability over a solution or semisolid formulation. A comprehensive understanding of the solid forms of
all the materials involved in drug formulation, including the drug and excipients, is very crucial for successful drug development.
Solids can be broadly classified into crystalline and amorphous types based on the presence or absence of long-range order. Amor-
phous solids do not possess long-range order and are known to be chemically and thermally less stable than crystalline solids. They
have a high tendency to convert to a more stable crystalline form and, hence, are generally less preferred in drug formulations.
However, there are instances where an amorphous form has been used as a strategy to improve bioavailability of poorly soluble
drugs as they possess higher solubility and faster dissolution rates than a crystalline form. Some of the well-known examples of
marketed amorphous drug formulations include zafirlukast (AccolateÒ), cefuroxime axetil (CeftinÒ), valsartan (DiovanÒ), and
quinapril hydrochloride (AccuprilÒ).
Internal arrangements of molecules in crystal structure, crystal habit (or morphology), and crystallite size play an important role
in determining the physicochemical properties of a crystalline solid (Table 1). Crystal habit (or the aspect ratio) of crystallites is
governed primarily by its internal structure, that is, molecular packing and intermolecular interactions present within the crystal.
Besides this, crystallization conditions such as solvent, additives, temperature, and pressure also play an important role in control-
ling the morphology and size of crystals. Both crystal habit and size are very important from the industrial manufacturability point
of view as they can affect properties such as filtration, drying, compression, tableting, flow characteristics, and the dissolution rate of
a drug. The internal arrangement of molecules in a crystal is of prime importance as it has major influence on properties like solu-
bility, dissolution rate, stability (chemical, thermal, and mechanical), and hygroscopicity properties of a drug.
Comprehensive Supramolecular Chemistry II, Volume 5 http://dx.doi.org/10.1016/B978-0-12-409547-2.12570-3 283
Comprehensive Supramolecular Chemistry II, 2017, 283–309

284 Crystal Polymorphism in Pharmaceutical Science
Table 1 Physical properties that differ among various solid phases
Packing properties Kinetic properties

Molar volume and density Dissolution rate
Refractive index Rates of solid-state reactions
Conductivity, electrical, and thermal Stability
Hygroscopicity
Surface properties
Thermodynamic properties Surface free energy
Melting and sublimation temperature Interfacial tensions
Internal energy (ie, structural energy) Habit (ie, shape)
Enthalpy (ie, heat content)
Heat capacity Mechanical properties
Entropy of the solid phase Hardness
Free energy and chemical potential Tensile strength
Thermodynamic activity Compactibility and tableting
Vapor pressure Handling, flow, and blending
Solubility
Spectroscopic properties
Electronic transitions (UV–Vis absorption spectra)
Vibrational transitions (IR and Raman spectra)
Rotational transitions (far IR or microwave absorption spectra)
Nuclear spin transitions (nuclear resonance spectra)
Crystalline solids (both single component and multicomponent) are known to exist in multiple forms. These forms differ in the
internal arrangement of molecules in the crystal structure and are known as polymorphs. Polymorphs show significant variations in
their physical and chemical characteristics. Solubility and dissolution properties of polymorphs are directly related to the bioavail-
ability of a drug and hence are of prime interest to the pharmaceutical industry. The solubility ratio between two polymorphs is
generally found to be less than two; however, in certain cases, it can be significantly higher.1 Therefore, the phase purity is consid-
ered an equally important quality attribute of the solid form of a drug besides its chemical purity. The presence of an unwanted
polymorphic phase can be a serious issue of concern to the pharmaceutical industry. The screening, identification, and character-
ization of various solid forms present in the bulk solid are therefore very important for resolving any phase purity issues at the pre-
formulation stage. The common phase impurities present in a (chemically pure) single-component solid drug sample may
correspond to a mixed crystalline phase containing polymorphs or an amorphous (or a polyamorphous) solid phase.2,3 The situ-
ation in multicomponent formulations of drugs developed based on salt, cocrystal, or solvates is even more complex as they are also
known to exhibit polymorphism. All these crystalline phases are considered an integral part of the crystalline phase space of a drug
(also termed as the structural landscape of a drug).4 Antiretroviral drug ritonavir represents a classic example of the occurrence of an
undesired polymorphic phase leading to its temporary withdrawal from the market. Phase purity of a drug can also lead to serious
patentability issues. The famous patent battle between GlaxoSmithKline (GSK) and Novopharm (now Teva Canada) over the rani-
tidine hydrochloride (ZantacÒ) formulation containing a polymorphic mixture serves as an excellent example that highlights the
underlying patentability and regulatory issues pertaining to polymorphism in drugs.
Polymorphic phase transitions in solids have direct implications on both processing and storage of the drug. There are numerous
factors that can induce a phase transition in solids such as temperature, pressure, humidity, particle size, impurities, and crystal
defects. Most commonly observed phase transitions in solids include a transformation between crystalline and amorphous phases,
transformation between two polymorphs, transformations between solvates and anhydrates, and formation of nonstoichiometric
solvates. Hence, it is very important to thoroughly investigate all solid phases of a drug, their interconversion behavior, and their
physicochemical properties for the selection of the optimal solid form with desired phase composition for a drug. Computational
approaches also play a significant role in the study of polymorphism, especially, crystal structure prediction (CSP) of polymorphs
and their stability comparisons. Some of the recent advancements in the CSP methodology and lattice energy computation
approaches that are relevant to crystal polymorphism studies are also discussed in this book chapter.
5.13.1.2 Definition and General Classification/Types

Polymorphism is widely prevalent in pharmaceutical solids. About 50% of known drug compounds are known to be polymorphic.
Polymorphism in drugs has been a very popular topic of many reviews,5,6 book chapters,7–11 and monographs12–17 published
earlier. Polymorphs are considered as the supramolecular isomers or super isomers of a compound that differs in their molecular
arrangements in the supramolecule, that is, the crystal.18 These differences in molecular packing arrangements can have origins in
the molecular geometry (different conformations or tautomers) or primary supramolecular recognition modes (different synthons)
and are classified, namely, as conformational, tautomeric, and synthon polymorphs (Fig. 1).

Crystal Polymorphism in Pharmaceutical Science 285
Figure 1 Some examples of polymorphism in drugs depicting different polymorph types. (A) Tautomeric polymorphism in omeprazole: figure
shows the two tautomers in equilibrium. (B) Conformational polymorphism in mefenamic acid: figure shows a molecular overlay of conformers
observed in form I (red), form II (green), and form III (blue). (C) Synthon polymorphism in carbamazepine: figure shows the amide dimer (form IV)
and catemer (form V) synthon present in the two polymorphs.
Compounds containing rotatable bonds can exist in various conformations in different polymorphs. This phenomenon is
termed as conformational polymorphism.19 The relative population of various conformers (generally, designated by a distinct potential
energy minimum) of a compound present in the solution varies with solvent, temperature, and other experimental conditions. The
supramolecular environment around the molecule in the crystal also plays a significant role in stabilizing a metastable molecular
conformation in the crystal. Compounds containing conformationally flexible groups such as –OH, NH2, and COOH deserve
a special mention as they are considered highly polymorphic as these groups possess a unique combination of flexibility and strong
hydrogen bond formation ability.20 Some of the well-known examples of conformational polymorphism in drugs include ritano-
vir,21 venlafaxine hydrochloride,22 olanzapine,23 temozolomide,24 furosemide,25 aripiprazole,26–29 nimesulide,30 tolbutamide,31
tolfenamic acid,32,33 mefenamic acid,34 and flufenamic acid.35 The 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile,
a pharmaceutical precursor of drug olanzapine, popularly known as ROY (red–orange–yellow), has the highest number of (10)
polymorphic forms known.36
Tautomeric polymorphism represents a special case of polymorphism in which crystal forms of distinct tautomers are isolated from
a solution or melt of rapidly interconverting tautomers present in equilibrium at a given temperature. The tautomer interconversion
rate is highly dependent on factors such as temperature, solvent, and pH. Some of the representative examples of tautomeric poly-
morphism in drugs include ranitidine hydrochloride,37 omeprazole,38 triclabendazole,39 piroxicam,40 and fenobam.41
Hydrogen bonding functionalities present in the compound are known to form specific intermolecular interactions that consti-
tute the basic structural unit of a crystal. These structural building blocks are popularly known as supramolecular synthons, for
example, a carboxylic acid dimer synthon.42 These synthons represent the primary chemical and geometric recognition modes of
a compound as they are known to contain information on kinetic factors involved in crystal nucleation and growth. The occurrence
of an alternate supramolecular synthon-directed molecular packing in polymorphs is termed as synthon polymorphism. Unlike the
conformational and tautomeric polymorphs, which mostly results from differences in molecular geometry, a variation in supramo-
lecular synthon in polymorphs may have deep mechanistic implications. The occurrence of synthon polymorphism in a compound
indicates the existences of competing crystallization pathways.43 Some representative cases of drugs showing synthon polymor-
phism include temozolomide,24 sulfathiazole,44 furosemide,25 pyrazinamide,45 and carbamazepine.46
5.13.1.3 Pseudopolymorphism and Polymorphism in Other Multicomponent Systems

The inclusion of water or other solvent molecules into the crystal lattice or during crystallization is a common phenomenon
observed for many drugs. The hydrate or solvate crystal forms of a compound are sometimes also termed as pseudopolymorphs.
Pseudopolymorphism phenomenon is related to the occurrence of alternate crystal forms of a compound that are obtained with
different types or stoichiometry of solvent molecule(s) in the crystal lattice.47 The term pseudopolymorphism is of particular

relevance in the pharmaceutical industry as they are considered equivalent to polymorphs from the regulatory and patentability
point of view.48 The famous patent battle between SmithKline Beecham and Apotex (discussed later in section Regulatory and
Patentability Aspects of Drug Polymorphs) on the anhydrate and hydrate forms of the blockbuster antidepressant drug Paxil
(paroxetine hydrochloride) is an important example that highlights the close similarity between polymorphs and pseudopoly-
morphs of the drug.
The use of cocrystals in drug formulation is new to the pharmaceutical industry; it has gained special attention in recent years as
they provide new routes for altering the physicochemical properties of a drug.49,50 Like single-component systems, polymorphism is
quite common in multicomponent solids. However, there are not many examples reported in the literature on polymorphism in
drug cocrystals. Some of the recently reported examples of polymorphism in pharmaceutical cocrystals include ethenzamide–gen-
tisic acid (trimorphic),51–53 carbamazepine–pyridine carboxamide,54–57 caffeine–carboxylic acid,58,59 isoniazid–hydroxycinnamic
acid,60 temozolomide–4,40 -bipyridine-N,N0 -dioxide,24 piroxicam–4-hydroxybenzoic acid,61 meloxicam–salicylic acid,62 furose-
mide–nicotinamide (pentamorphic),63 and dapsone–flavone cocrystals.64
5.13.1.4 Ostwald’s Rule of Stages, Concomitancy, Intergrowth, and High Z 0 Polymorphs

Ostwald had extensively studied the kinetics of crystallization from solution. His observation had been formulated as Ostwald’s rule
of stages, according to which, “when leaving a given metastable state and in transformation to another state, a given chemical system
does not seek out the most stable state, rather the nearest metastable one that can be achievable with minimum loss of free
energy.”65 This rule relates to the appearance of a metastable form during crystal nucleation in the initial stages followed by a trans-
formation to a more stable form (not always necessarily corresponding to the thermodynamically most stable form). A closely
related phenomenon is the case for a disappearing polymorph; the term disappearing polymorph corresponds to a situation
when a previously isolated polymorph fails to crystallize in subsequent attempts.66 Generally, these lost forms are considered meta-
stable and become extinct once a more stable form is isolated. Intentional or unintentional seeding in such situations may also lead
to disappearance of a polymorph (eg, ritonavir polymorphs). However, it is now widely accepted that a disappearing polymorph
may be obtained provided suitable experimental conditions are met or enforced. Some of the well-known examples and the strat-
egies employed in the recovery of disappeared polymorphic forms are presented in a recent review by Bucar et al.67 However, the
existence of a concomitant polymorph, that is, the simultaneous crystallization of multiple polymorphs of a compound from the same
crystallization vessel under identical experimental conditions,68 is considered as an exception to Ostwald’s rule as it defies the
cascading evolution theory of crystal forms. Intergrowth polymorphs present another very interesting and challenging case of crystal
polymorphism. It refers to a situation when two polymorphs of a compound are found present as distinct structural domains within
the same single crystal. The coexistence of multiple domains of polymorphs poses challenges to the polymorph characterization
methods. Some of the well-documented cases of intergrowth polymorphs in drugs include aspirin (forms I and II)69,70 and felodi-
pine (I and II).71
The occurrence of high Z0 polymorphs, that is, the existence of more than one molecule in the asymmetrical unit (Z0 ), represents
another interesting feature in crystal polymorphism.72 Although a large number of polymorphic systems were reported in the liter-
ature, however, the existence of polymorphic systems with Z0 > 1 is no more than 12% in the Cambridge Structural Database.73 The
existence of high Z0 in polymorphic form is systematically studied and summarized by Steed in a recent review.72 According to
Desiraju,74 structures with Z0 > 1 often represent kinetic forms as opposed to the most stable thermodynamic form. Therefore,
a systematic analysis of these high Z0 crystal structures can provide crucial information about the crystallization process.75 These
structures are also described as fossil relics of the fastest growing crystal nucleus.76 Various factors that are considered responsible for
the formation of high Z0 polymorphs include awkward molecular shape leading to packing difficulties, existence of pseudosymme-
try, synthon frustration, and equienergetic conformations. A few representative examples of polymorphic high Z0 systems of drug
are efavirenz,77 phenylacetylene,75 venlafaxine hydrochloride,22 carbamazepine,78 phenobarbital,79 paracetamol,80 etc.
5.13.2 Experimental Approaches for Polymorph Screening and Characterization

5.13.2.1 Polymorph Screening Methods
Polymorphs are usually encountered under varying crystallization conditions; therefore, it is considered that the chances of finding
new polymorphs increase with the number of crystallization experiments performed under different conditions.81 The conventional
methods of polymorph screening include solvent evaporation, mechanical grinding (neat and liquid assisted), screw extrusion,
sublimation and melt crystallization, Kofler approach, and by the desolvation of solvates. With advancements in instrumentation,
several new techniques have been developed for polymorph screening that include additive-induced polymorph nucleation more
specifically polymer-induced heteronucleation (PIHn) and self-assembled monolayer (SAM), pressure-induced crystallization,
supercritical fluids, and use of robotics for high-throughput crystallization studies.
Mechanochemical methods (manual or ball mill grinding) for crystallization in the absence (neat grinding) and in the presence
(liquid-assisted grinding (LAG)) of a small amount (mL) of liquid commonly known as grinding method are used extensively for
preparation of various pharmaceutical salts,82 cocrystals,58,83,84 solvates,85 and polymorphs during the last two decades.58,83,86
The mechanism of crystallization during grinding and its advantages with respect to solution crystallization have been extensively
studied in the recent literature.87–89 Screw extrusion is another important mechanochemical method that has also been found useful

for obtaining polymorphs. It involves a shearing process; the instrument consists of a feeder, a barrel containing two corotating or
counter rotating screws, and a die at the end of the barrel. The screw provides a shearing action to the material inside the barrel. The
shear pressure depends on the screw configuration, screw speed, and different zones of the extruder barrel. Depending on the
temperature maintained during the extrusion process, they can be referred to as high-temperature extrusion (HTE) (when temperature
is maintained just below the melting point of the material) and hot-melt extrusion (HME) (when temperature is maintained at the
melting point of the material). This process can be applied to specific solid materials to induce polymorphic phase transformations
by the application of high temperature and pressure (shear). By controlling the temperature of the extruder and maintaining the
rotational speed of the two screws, one can prepare a specific metastable polymorph using this technique. A liquid-assisted extru-
sion can also be performed, which gives further advantages especially in the cocrystallization studies.90,91 Very few examples were
reported in the literature where polymorphic forms were prepared using the screw extrusion method.92–94
The addition of a small amount of a compound that is structurally similar to the parent compound (intentional seeding) or the
presence of an impurity (unintentional seeding) can sometimes result in new polymorphs. This method is commonly known as
additive-induced polymorph nucleation. There are many examples that report a serendipitous nucleation of a polymorph during
attempted crystallization with other compounds, for example, isolation of aspirin form II on crystallization with levetiracetam
or acetamide,95 olanzapine form IV with nicotinamide,96 paracetamol form II with substituted carboxylic acid,97 felodipine
form II with isonicotinamide,98 nicotinamide, and isonicotinamide with antitubercular drug isoxyl.99 However, there are not
many examples in the literature29,100,101 that report a deliberate use of additives for obtaining the desired polymorph in drugs. Lei-
serowitz and coworkers102–104 carried out systematic studies on the use of additive to control or induce polymorph formation and
have provided a basic model for this method. The structural similarities of the additive with the parent compound are exploited in
the selective inhibition of the growth of a particular face of the embryonic crystal of the parent compound, which may result in the
crystallization of the desired polymorph. Similarly, the use of polymers (polymer-induced heteronucleation) or surfactants (SAM)
as additives has been reported for polymorph screening. In the polymer-supported or polymer-induced heteronucleation, commercially
available polymers and combinatorically synthesized cross-linked polymers are used that serve as a platform for crystal growth for
different polymorphs. This technique has been used successfully to obtain polymorphic forms of various drugs such as acetamin-
ophen, sulfamethoxazole, carbamazepine, and pharmaceutical intermediate 5-methyl-2-[(2-nitrophenyl)amino]-3-
thiophenecarbonitrile (ROY) in the recent past.105–107 SAMs are ordered molecular assemblies formed by adsorption of a surfactant
on a surface with a specific affinity of its head group. Molecules used for SAM formation contain a functionalized head group, back-
bone part, and end group. The functionalized head group acts as a template for heterogeneous nucleation and crystallization of
various materials including pharmaceutical solids.108–111 The process of preparing SAM surfaces is shown in Fig. 2. More informa-
tion on the formation of self-assembled monolayers can be obtained from Ulman’s review on this topic.112
Thin gold foils are the most suitable substrates for preparation of SAM surfaces. Nucleation of different polymorphs can be
induced by tuning various SAM characteristics such as, island size (to alter supersaturation rate), number of islands (to improve
probability of polymorph detection) together with substrate properties such as concentration, pH etc.108–111 Appearance of meta-
stable polymorphs in certain cases is due to statistical reasons as a large number of islands mimic multiple crystallization
Figure 2 Process of preparing SAM surface for crystallization or organic solids. Adapted with permission from Chem. Rev. 1996, 96, 1533–1554.
Copyright 1996 American Chemical Society.

Figure 3 (A) Patterned substrate of SAM showing small square gold islands (more than 2000 islands) having dimensions within 500 mm; (B) small
portion of the islands containing single crystals with enlarged view. Reprinted with permission from Cryst. Growth Des. 2008, 8, 108–113. Copyright
2008 American Chemical Society.
experiments. A patterned substrate of SAM prepared using gold foil containing small square gold islands used for crystal nucleation
is shown in Fig. 3.
Crystallization in supercritical fluid (SCF) is an innovative technology for polymorph screening and preparation of a specific
physical form of pharmaceutical solids. Supercritical state is the point where the density of a gas and that of a liquid are the
same; therefore, they can be considered as an intermediate stage between gas and liquid phases. All gases can form SCF; however,
CO2 is the most commonly used gas to prepare SCF for crystallization of various solids including pharmaceutical materials. By
proper adjustment of operational conditions such as pressure, temperature, and flow rate, a desired solid-state form can be gener-
ated. Various processes used for crystallization using SCF can be divided into two groups: (i) processes using supercritical fluid as
a solvent such as rapid expansion of a supercritical solution into a liquid solvent and (ii) processes using supercritical fluids as an anti-
solvent that include gaseous antisolvent, particles by compressed antisolvent, and solution-enhanced dispersion with supercritical fluids.
Due to the versatility, high compressibility, and diffusivity, fine-tuning of pressure and solvent evaporation rate result in great
control over specific physical forms of pharmaceutical substance using SCF that made this technique an excellent alternative to poly-
morph screening and preparation during the last two decades.113–117
One of the most advanced polymorph screening methods is high-throughput (HT) crystallization where thousands of crystalliza-
tion experiments can be carried out using an automated device in a lesser time period with few grams of sample (Fig. 4). The solids
obtained from the HT crystallization can be analyzed using various characterization techniques such as PXRD and FT-Raman and
categorized into definite clusters (Fig. 5).
Figure 4 Schematic representation of the workflow of an HT crystallization system. Reprinted with permission from Adv. Drug Deliv. Rev. 2004, 56,
275–300. Copyright 2004 Elsevier.

Figure 5 Cluster diagram of PXRD pattern similarity for MK-996 from HT polymorph screen. Clusters are indicated by red-colored regions and
represent different solid forms. Reprinted with permission from Cryst. Growth Des. 2003, 3, 927–933. Copyright 2003 American Chemical Society.
The major advantages in using an HT-screening technologies include (i) performing large number of crystallization experiments
in a lesser time span, (ii) requirement of less man power, (iii) very small quantity of material required, and (iv) enhanced proba-
bility of obtaining more number of crystal forms compared with traditional screening method.118,119
5.13.2.2 Characterization of Polymorphic Forms

Understanding the polymorphic behavior of all compounds used in a drug formulation, their characterization, stability relation-
ships, and the study of polymorphic phase transformations is essential, particularly for the pharmaceutical industry. Various
solid-state techniques can be used in the characterization of polymorphs. Among them, single crystal X-ray diffraction (SCXRD),
powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR), Raman and Near-infrared (NIR) spectroscopy, solid-state
NMR (ss-NMR), differential scanning calorimetry (DSC), more recently nanoindentation, atomic force microscopy (AFM), and
transmission electron microscopy (TEM) are of particular importance.
5.13.2.2.1 X-ray diffraction

SCXRD and PXRD are the utmost important characterization techniques for studying polymorphs. Distinct polymorphic forms are
characterized by distinct powder diffraction patterns; therefore, PXRD is also considered as a very important fingerprint tool for
studying polymorphism. It is commonly used to obtain information about the phase purity of a bulk solid sample and is very infor-
mative in the qualitative and quantitative analysis of mixed polymorphic phases. The advancement in the powder structure solution
methods, variable temperature, pressure and humidity attachments, etc. makes this instrument a versatile tool for analyzing poly-
morphic phase transformations and obtaining information about the phase stability and hydration behavior. In the recent litera-
ture, a large number of new polymorphic phases have been identified and successfully determined their structural information86,120
based on powder data.
SCXRD is the ultimate technique for obtaining atomic-level structural information and helps in the complete characterization of
polymorphs. However, it requires suitable size single crystals and is not preferred for the analysis of bulk sample. The characteriza-
tion of two intergrowth polymorphs of aspirin (Fig. 6) by a very careful analysis using SCXRD serves as an extreme case wherein the
two polymorphic phases present in the same crystal had been successfully identified.
5.13.2.2.2 Thermal methods

DSC is a thermoanalytic technique where change in heat required to increase the temperature of a sample w.r.t. reference is
measured as a function of temperature. The process, which leads to the absorption of heat such as solvent loss, phase transition,
and melting, results in endothermic peaks, whereas release of heat such as crystallization and chemical reaction yield exothermic
peaks. DSC is a very useful technique to characterize polymorphs, calculate their relative stability, and correlate between various
polymorphic forms (enantiotropy or monotropy). More advanced and modified versions of DSC instrumentation, namely, modu-
lated temperature DSC121 and hyper-DSC, can give much more information compared with the trivial one. Modulated DSC helps in

Figure 6 Interlayer arrangement of intergrowth polymorph A (centrosymmetrical C–H/O dimers colored in red) and B (C–H/O catemers extend-
ing along 21 screw axes colored in blue) of aspirin crystal with identical O–H/O hydrogen-bonded layers. Reprinted with permission from Angew.
Chem. Int. Ed. 2007, 46, 618–622. Copyright 2007 John Wiley and Sons.
separating overlapping transitions in the case of polymorphic forms, direct measurement of heat capacity, improved sensitivity for
detecting weak transition, etc. The utility of hyper-DSC is to study polymorphic behavior of the metastable form. Due to the high
scanning rate (usually 300–500 C min 1), it can inhibit phase transitions and help to calculate enthalpy of fusion of a metastable
form (Fig. 7). This method also helps to detect the presence of polymorphic impurities in a sample lower than 10% (w/w).122,123
Hot-stage microscopy is a thermal technique used for the identification of phase transformation, solvent loss, melting and subli-
mation events, etc. A microscope coupled with a temperature-controlled stage facilitates observation of any physical changes
possible for a system. Although it is very useful to characterize polymorphic form/phase transformation,53,124–127 additional instru-
mentation techniques are required to characterize the system as, in some cases, the same crystalline phase can have more than one
morphology. Hot-stage microscopy images of two polymorphic forms of sulfathiazole crystals and their melting events are shown
in Fig. 8.
5.13.2.2.3 Spectroscopic methods

Due to the difference in crystal packing, polymorphs can be distinguished using various solid-state characterization techniques such
as FT-IR, FT-Raman, and ss-NMR. FT-IR spectroscopy is widely used in the pharmaceutical industry to distinguish polymorphs. It
can give much information about the presence of hydrogen bonding. For example, the presence of carboxylic acid dimer and free
amine group in the neutral form of anthranilic acid and intermolecular H-bonded ammonium carboxylate synthon in zwitterionic
form can be distinguished easily using FT-IR spectroscopy.128 Nangia et al. used Fourier transform infrared (FT-IR), Raman and
Near-infrared (NIR) spectroscopy to distinguish various polymorphic forms of pharmaceutical solids in the recent
literature.25,30,45,129,130 Desiraju and coworkers extended this technique further to characterize the presence of various homo-
Figure 7 Hyper-DSC of carbamazepine form III at different scan rates. Melting of the metastable form can be visualized separately only at high scan
rate. Reprinted with permission from Thermochim. Acta 2004, 417, 231–237. Copyright 2004 Elsevier.

Figure 8 Image of sulfathiazole polymorphs (forms I and II) and their melting event captured using HSM analysis. Reprinted with permission from
J. Therm. Anal. Calorim. 2009, 99, 609–619. Copyright 2009 Springer.
and heteronuclear supramolecular synthons present in a polymorphic cocrystal system of 4-hydroxybenzoic acid-4,40 bipyridine
(2:1) in a recent report.131 Tetramorphic pyrazinamide is an excellent example45 to discuss here, as SCXRD, PXRD, DSC, FT-IR,
Raman, NIR, and all instrumental techniques were used to characterize/determine the relative stability of all polymorphic forms
over a temperature range 273 C to 190 C (Fig. 9).
Nuclear magnetic resonance is one of the essential techniques to determine molecular structure in solution. Development of
magic-angle spinning coupled with cross polarization advances the solid-state characterization of pharmaceutical solids due to
Figure 9 Energy vs temperature diagram of pyrazinamide polymorphs to show relative stability and phase transformation over a temperature
range 273 C to 190 C. At 273 C, d is the more stable form; between 25 and 155 C, the a form has the lowest free energy. The d and a forms
convert to the g form on heating above 130 C and 155 C, respectively. The g form is more stable after 155 C until it melts at about 190 C. Reprin-
ted with permission from Cryst. Growth Des. 2010, 10, 3931–3941. Copyright 2010 American Chemical Society.

its nondestructive and noninvasive nature, especially within a formulated product. Small changes in conformation and/or local
electronic structure cause observable differences in ss-NMR to characterize polymorphic forms, quantitative analysis132 of polymor-
phic mixture, and the presence of amorphous content in a crystalline solid.133 In the recent literature,134–137 a large number of case
studies have been reported based on ss-NMR spectroscopy as a characterization tool for polymorphic pharmaceutical solids.
5.13.2.2.4 AFM, nanoindentation, and TEM methods

AFM is a type of scanning probe microscopy that has emerged as a tool for imaging and measuring features at nanoscale level. In
recent years, AFM has been used extensively to study various aspects of molecular crystals such as crystal growth mechanism, disso-
lution, crystallization, and additive-induced growth inhibition. Danesh et al. in two separate reports138,139 used the amplitude and
phase to distance (a-p,d) curves of intermittent contact mode atomic force microscopy (IC-AFM) as a fingerprint tool to distinguish
polymorphic systems of cimetidine (forms A and B). Cao and coworker reported140 force curve measurements for sulfamerazine
forms I and II as a differentiating tool for polymorphic forms. In a recent report, Thakuria et al.141 used AFM height image as
a tool to distinguish two polymorphs of caffeine–glutaric acid cocrystals (form I and form II) and correlate them with their crys-
talline packing arrangement (Fig. 10). They also used these step heights as a fingerprint to study polymorphic phase transformation
under high humidity.
Nanoindentation is used as an effective method to measure mechanical properties of solids with high precision, on extremely
small volumes of solid. The first report of nanoindentation as a characterization tool to distinguish polymorphs (sulfathiazole
forms I, II, and III) was by Picker-Freyer and coworkers.142 Although nanoindentation is quite familiar in the material industry,
the use of this technique to measure mechanical properties of organic solids, specifically polymorphs, is popularized by Desiraju
and coworkers in recent years with their report on polymorphic forms of aspirin143 (Fig. 11) and a review thereafter.144 In 2013,
Reddy et al.145 used nanoindentation for the first time to distinguish a cocrystal polymorphic system of caffeine–4-chloro-3-
nitrobenzoic acid.
TEM is a useful technique to characterize the presence of minor phases in a mixture in exceptionally small amount, provided that
a suitable crystallite is located. Diffraction mode of TEM can give information about symmetry and crystal structure. However, this
method is not routinely used for organic molecular compounds as they are sensitive to the electron beam and get decomposed
within a few minutes. A highly sophisticated technique of combined CSP/TEM approach has been developed by Eddleston
et al.146,147 to characterize polymorphs at the nanoscale level. In their report, they used TEM electron diffraction for identification
of polymorphic forms of paracetamol, scyllo-inositol, and theophylline by a process of indexing diffraction pattern and comparing
their results with CSP to identify the specific form (Fig. 12).
Combined TEM/CSP approach is quite useful for situations in which traditional X-ray-based approaches to crystal structure
determination are not applicable, for example, if only a trace amount of material is available for analysis, or the crystal phase of
interest is present as a mixture with other forms. However, the usefulness of this technique depends on the organic system and expe-
rienced operator to get satisfactory result.
Figure 10 (A) IC-AFM height image of the (001) surface of a caffeine–glutaric acid from I crystal; (B) IC-AFM height image of the cleaved (001)
surface of a form II crystal. Reprinted with permission from Angew. Chem. Int. Ed. 2013, 52, 10541–10544. Copyright 2007 John Wiley and Sons.

Figure 10 (continued).
Figure 11 Representative P–h curves for all three faces examined with pop-ins indicated by arrows for the loading curve of aspirin polymorph I.
Reprinted with permission from Chem. Sci. 2011, 2, 2236–2242. Copyright 2011 Royal Society of Chemistry.
5.13.3 Impact of Polymorphism on the Physicochemical Properties of Drugs
Differences observed in the molecular packing and intermolecular interactions present in polymorphs of a drug result in alteration
in its physicochemical properties. This section highlights examples of a few polymorphic drug systems and their influence on
various solid-state properties.
5.13.3.1 Solubility
Solubility is a thermodynamic property and related to free energy; therefore, different polymorphs will have different solubility
values in a solvent system at a particular temperature. As temperature is a function of solubility, at a specific temperature (except
for transition temperature (Tt)), a metastable polymorph has higher solubility compared with a stable polymorph. It is this differ-
ence that causes differences in dissolution rates leading to solution-mediated polymorphic phase transformation. For such cases,
intrinsic dissolution rates give much more information about the metastable phase.
5.13.3.2 Dissolution Rate and Bioavailability

Orally administered solid dosage forms generally undergo disintegration, dissolution, and absorption to enter the bloodstream and
finally reach the site of action. Therefore, solubility and dissolution are two important factors for the therapeutic action of a drug

Figure 12 Electron diffraction pattern of the < 011> zone axis of form I of paracetamol. b) Simulated electron diffraction pattern from the <011 >
zone axis of the computationally derived paracetamol crystal structure AM30. Reprinted with permission from Chem. Eur. J. 2013, 19, 7874–7882.
Copyright 2013 John Wiley and Sons.
substance. Dissolution involves the breaking of existing interactions present in the solid and formation of new interactions with
solvent, generally water. Solid dissolution generally involves two sequential steps: first one is the solvation (interaction between
solid and solvent molecules resulting in solvated molecules) and the second step is the mass transport of solvated molecules
from the solid–liquid interface to the bulk solution. Overall dissolution is governed by solubility and transport processes.
Intrinsic dissolution rate
When agitation intensity and surface area are fixed, dissolution rate can be viewed as a property of the solid. This loosely defined
property is called the “intrinsic” dissolution rate. Due to the close relationship between solubility and intrinsic dissolution rate,
measuring the intrinsic dissolution rate becomes an alternative method to estimate the solubility of pharmaceutical solids that
convert easily to solvates or undergo polymorphic transformation during equilibrium solubility measurement.
The dissolution rate is given by
dQ
¼ 1:95D2=3 Cs u1=6 u1=2 R2
dt
where D is the diffusion coefficient, Cs is the solubility, u is the kinematic viscosity, u is the rotational speed, R is the disk radius.
In the convective–diffusion method, diffusion layer thickness can be calculated using the equation
=3
h ¼ 1:61D1 u1=6 u1=2
Anti-HIV drug ritonavir serves as an instructive example of pharmaceutical polymorphs exhibiting distinct solubility and disso-
lution rate properties. Chemburkar et al.148 carried out a structural analysis to compare the solubility of the two polymorphs of
ritonavir. The presence of stronger hydrogen bonds and better crystal packing leads to lower solubility and dissolution of form
II compared to form I (Fig. 13).
Mebendazole is a benzimidazole derivative having anthelmintic properties used in the treatment of ascariasis, uncinariasis,
oxyuriasis, trichuriasis, and more than one worm infection at a time. It exists in three polymorphic forms, namely, A, B, and C.
The solubility of the three forms in physiological media is in the order form B > form C > form A.149 Among them, form A is
not having anthelmintic activity alone, or when present above 30% in polymorphic mixture, form B is toxic due to its high solubility
and dissolution rate. Therefore, form C with moderate solubility is the preferred form without possible toxicity.
Pudipeddi and Serajuddin1 carried out a survey on the solubility ratio of reported polymorphs of 55 compounds (81 solubility
ratios due to the presence of multiple polymorphs) of pharmaceutical relevance. From their results, it was observed that the majority
of the polymorphs had solubility ratio less than two, except the case of premafloxacin (I/III) where the solubility ratio in ethyl
acetate is unusually high (a factor of 23.1).150
In the recent literature, Nangia151 and Rasmuson152 independently reported solubility and dissolution rates of curcumin,
the active curcuminoid ingredient in turmeric. Nangia and coworker prepared two new polymorphs of curcumin (forms II
and form III) using solution crystallization. The newly synthesized form II has better solubility and dissolution rate compared
to the existing polymorph I. Rasmuson compared the solubility of form I (in EtOH and ethylacetate) and form III (in EtOH,
Fig. 14).

Figure 13 Hydrogen bonds present in ritonavir form I and form II crystal structures.
Figure 14 Experimentally measured values of the solubility of curcumin form I in EtOH and EtOAc and of curcumin form III in EtOH (symbols).
Reprinted with permission from J. Pharm. Sci. 2015, 104, 2183–2189. Copyright 2015 Elsevier.
In another report, Mishra et al.153 correlated solubility and mechanical properties of two polymorphic systems, curcumin and
sulfathiazole. From their data, it has been observed that hardness (H) is inversely proportional to the solubility of a polymorph, that
is, softer polymorph is more soluble. The summary of the results can be shown in Fig. 15.
5.13.3.3 Hygroscopicity
Stability studies of a pharmaceutical material under different relative humidity (RH) conditions are well practiced in the pharma-
ceutical industry as the RH varies depending on geographic location and change in altitude across the globe that may cause physical
and chemical instability to a drug product. Moisture generally interacts with solids in four different ways, namely, adsorption,
absorption, deliquescence, and lattice incorporation. Under normal conditions, water molecules interact with the surface of a mate-
rial forming a monolayer. Under high humidity, it forms additional layers resulting in stronger interaction between water and the

Figure 15 Inverse correlations of hardness and solubility in (A) curcumin and (B) sulfathiazole polymorphs. Reprinted with permission from Cryst.
Growth Des. 2014, 14, 3054–3061. Copyright 2014 American Chemical Society.
solid surface that may result in chemical instability of the material. Particle size also influences moisture uptake by increasing surface
area of adsorption. As a result, small-sized particles (high surface area) can adsorb a large amount of water compared with larger
crystals. When water molecules incorporate into the crystal lattice, it leads to formation of hydrates. A most significant mode of
water–solid interaction is absorption, where water molecules penetrate into the bulk solid. When the solid is highly soluble in water
and a certain relative humidity (RH) is exceeded (deliquescent point), it leads to the formation of a saturated solution around the
solid known as “deliquescence” phenomenon. During the formulation process and milling, generally, drug are exposed to moisture,
resulting in a small amount of moisture being incorporated into the drug. Therefore, moisture uptake and hygroscopicity studies
using dynamic vapor sorption and thermogravimetric analysis are routine processes in the pharmaceutical industry. Since water is
a polar solvent having both hydrogen bond donor and acceptor groups, it can interact with the solid surface by forming hydrogen
bonds. Therefore, due to different packing arrangements and intermolecular interactions, polymorphs do behave differently to
exposed humidity.
Trask et al. reported59 two cocrystal polymorphs, caffeine–glutaric acid forms I and II using LAG and solution crystallization.
Hydration stability under various relative humidities showed that form I was stable only at 0% RH, whereas it converted to
form II at all other humidity conditions. Although form II was relatively stable, at 98% RH, it dissociates into caffeine hydrate after
one week. Stabilities of the two polymorphs under various RH conditions are listed in Table 2.
In a recent report, Thakuria et al.141 explained the relative hydration stability of these two polymorphs based on their crystal
packing. In case of form I, the linear chain of caffeine–glutaric acid molecules stacked parallel to each other resulting in slip planes
along the (001) face. Due to the presence of slip planes, these layers are much more exposed to atmospheric moisture compared to
form II where these caffeine–glutaric acid layers are tilted and form a slightly corrugated layer. As a result, form I is highly unstable
and undergoes polymorphic phase transformation followed by dissociation.
Vogt et al.154 in their study of a drug molecule {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic
acid used for the treatment of overactive bladder to open the so-called “BK” (big potassium) channels and help regulate bladder
activity observed that the dimorphic system shows different behaviors under high relative humidity (RH). From gravimetric vapor
sorption (GVS) analysis, it was observed that form I absorbed more than 4% (w/w) water at 90% RH, and desorption was relatively
Table 2 Relative stabilities of caffeine–glutaric acid cocrystal polymorphs (forms I and II) under various
experimental RH conditions
Observed RH stability
Material Condition (% RH) 1 day 3 days 1 week 7 weeks
Form I 0 O O O O
43 O x x x
75 x x x x
98 x x x x
Form II 0 O O O O
43 O O O O
75 O O O O
98 O O x x

Figure 16 GVS isotherm obtained for form I and form II. (A) Significant uptake of water greater than 50% RH for form I; (B) negligible water
uptake over 0–90% RH in case of form II. Reprinted with permission from Inter. J. Pharm. 2009, 366, 1–13. Copyright 2009 Elsevier.
slow (Fig. 16A). This kind of behavior was generally observed in the case of hydrates; however, PXRD of the material confirms that
form I was hygroscopic in nature and did not show any phase transition (hydrate formation). In the case of form II, no evidence of
significant hysteresis in the absorption isotherm was observed (Fig. 16B), and the material was nonhygroscopic in nature. Therefore,
although form I is thermodynamically stable, form II is used for formulation due to its high physical stability and low conversion
rate.
Kobayashi and coworkers155 carried out a physicochemical study on carbamazepine polymorph (forms I and III) and pseudo-
polymorph (dihydrate). From the hygroscopicity study, it was observed that form III was quite unstable; it adsorbed 13.7% water
after 2 weeks and converted to carbamazepine dihydrate (13.2%). On the other hand, form I was relatively stable, adsorbing only
1.9% water (Fig. 17) under similar conditions and remaining as form I after 28 days of exposure to high humidity. The initial disso-
lution rate of all three forms was in the order of form III > form I > dihydrate. With time form III converted to dihydrate more
rapidly compared with form I, as a result, dissolution rate is decreasing over time.
Celiprolol hydrochloride, a beta-blocker used in the treatment of high blood pressure, exists in two polymorphic forms (forms I
and II). Form I was found to be less hygroscopic than form II.156 Form II absorbs about 3% moisture even at 37% RH within 1 h,
whereas form I is quite stable up to 80% RH. However, it converts to form II on exposure to high humidity (> 80% RH) over a period
of one month. Therefore, maintaining an appropriate humidity condition is very much essential for manufacturing the solid dosage
form of celiprolol hydrochloride.
Few other groups have studied relative stability of various pharmaceutical polymorphic systems such as S-bupivacaine hydro-
chloride,157 glutaric acid,158 and lactose159 under variable RH conditions. From these examples, it was observed that under high
humidity, pharmaceutical materials can undergo dissociation, polymorphic transformation, hydrate formation, and decomposition

Figure 17 Hygroscopicity study of carbamazepine polymorphs I (n) and III ( ) at 40 C and 90% RH. Reprinted with permission from Int. J. Pharm.
l
2000, 193, 137–146. Copyright 2000 Elsevier.
that may lead to loss of biological activity and patent infringement. Therefore, it is essential to carry out thorough stability study
under various RH conditions before launching a drug product in the market.
5.13.3.4 Chemical Stability

Chemical stability is of primary concern to pharmaceutical materials as degradation and reactivity to chemicals or light (photo-
chemical reaction) may lead to the loss of biological activity. When a drug substance is intrinsically chemically reactive or unstable,
during the formulation process, degradation can be accelerated in any of the following ways:
l Acceleration due to interaction with excipients
l Acceleration due to processing effects
l Acceleration induced by excipients (but not involving chemical reactions with the excipient)
Only a few cases have been reported in the literature that exhibit variable chemical stability with respect to pharmaceutical poly-
morphism. Carbamazepine is one such drug that is extensively studied in the literature with a large number of reported multicom-
ponent systems. The guest-free form of carbamazepine undergoes photo degradation leading to the photo product shown in Fig. 18.
Figure 18 Photodegradation products of carbamazepine.

Figure 19 Reaction between indomethacin and ammonia.
Matsuda et al.160 studied the kinetics of photodegradation of carbamazepine polymorphs. Based on their study, they postulated that
atmospheric water molecules on the surface of the material act as a catalyst for photodegradation. Upon irradiation using UV light
with intensity 12 Jm 2s 1 for 1 day, the rate of photodegradation of carbamazepine form II is 5.1 and 1.5 times faster than those of
forms I and III.
A similar study was carried out with furosemide polymorphs (forms I and II) by de Villiers and coworkers.161 From their analysis,
it was observed that form I was photochemically more stable than form II, especially under nitrogen atmosphere. Exposure of
sunlight resulted in the photolytic product 4-chloro-5-sulfamoylanthranilic acid (CSA) in significant concentration in both form
I and II powder samples. In the presence of nitrogen, furosemide form II led to the formation of mainly CSA as photolytic degra-
dation product and CSA and unidentified products in presence of oxygen.
It is often observed that a thermodynamically more stable polymorph is also chemically more stable. However, the higher ther-
modynamic stability which is generally attributed to a denser molecular packing in crystal (density rule), should not always be
correlated to its chemical stability. The chemical stability is also influenced by other factors such as crystal morphology and size.
Indomethacin162 is one of such example, where the metastable a form has higher packing density compared with the thermody-
namically stable g form and chemical reactivity toward ammonia gas does not follow the density rule. On exposure to ammonia
gas, the a form reacts much faster and the reaction is anisotropic and proceeds along the a-axis of the crystal lattice resulting in
a microcrystalline ammonium salt (Fig. 19), whereas the g form is inert to ammonia gas.
Looking into the crystal structure of the two polymorphs, it was observed that the metastable a form has three molecules of
indomethacin in the asymmetrical unit. Two symmetry-independent indomethacin molecules form a mutually hydrogen-
bonded carboxylic acid dimer, whereas the third indomethacin molecule is hydrogen bonded to one of the amide carbonyls of
the dimer. In 3-D packing, the carboxylic acid groups are exposed to the (100) faces and accessible to attack by ammonia gas. After
one layer of molecules reacts, the reactive groups in the subsequent layer are accessible to ammonia gas. As a result, the reaction
proceeds along the a-axis until ammonia gas has penetrated the entire crystal. On the other hand, in g form, centrosymmetrical
carboxylic acid dimers are shielded by hydrophobic groups and are nonaccessible to ammonia gas. Hence, the g form is inert toward
exposure of ammonia. From this example, it was observed that not only packing density but also intermolecular interactions,
exposed hydrogen bonds, nonhydrogen interactions, etc. also play an important role toward the chemical stability of a drug.
Stampa Diez del Corral et al. reported163 in a patent about stability at 40 C and 75% RH for two polymorphic forms A and B of
paroxetine maleate. Form B was found to be more stable toward degradation compared to form A, characterized using High perfor-
mance liquid chromatography (HPLC).
5.13.3.5 Mechanical Properties

Polymorphism can influence the mechanical behavior of a solid. Difference in crystal packing and hydrogen bond interactions
induces a polymorph to respond differently to mechanical stress. Although organic materials are not intended for mechanical
load, pharmaceutical materials experience mechanical stress during drug processing and development (blending, granulation, tab-
leting, etc.). These processes may lead to polymorphic phase transition, instability, solvate formation, etc. that may lead to patent
infringement for a particular polymorphic form. Therefore, it is necessary to study mechanical properties of all possible polymor-
phic phases of pharmaceutical solids. Summers et al.164,165 proposed a semiempirical rule to predict the effect of crystal packing of
polymorphs on their compressibility and bond strength, according to which a more stable polymorph due to its higher density is
expected to form stronger intermolecular interactions and be harder to deform. Therefore, better tablets can be prepared from a poly-
morph having weaker intermolecular interactions and lesser density, that is, from a metastable form. However, this statement is
a controversial one, as various factors such as the presence of slip planes, porosity, heat of fusion, compressibility (representing
bonding area), and compactibility (representing bonding strength) also contribute to tabletability of a material. A few case studies
are discussed here to analyze various factors influencing mechanical properties of pharmaceutical solids.
The reason for higher plasticity, that is, better compressibility and tabletability of sulfamerazine form I compared with the more
stable form II at room temperature, was found to be the presence of slip planes in their crystal lattice.166 Roberts et al. predicted
mechanical properties of two polymorphic systems: sulfathiazole167 (forms I and III) and carbamazepine168 (a and b forms) based
on an atom–atom potential model applied to lattice dynamics. Similarly, the analgesic drug paracetamol169 (acetaminophen) has
two metastable polymorphs (forms II and III), one of which (form II) has better tableting properties than the stable form I. Crystal
structure analysis reveals that the presence of a parallel hydrogen-bonding sheet of molecules along the c-axis results in slip planes,

Figure 20 Crystal structure of paracetamol (A) form I and (B) form II with slip planes along the c-axis.
which allow plastic deformation and hence better compressibility and tabletability in the case of form II, whereas form I lacks a slip
plane and contains herringbone type of crystal packing. Single crystals of paracetamol form III could not be prepared to have struc-
tural information. The crystal structures of paracetamol forms I and II are shown in Fig. 20. Although having better compressibility,
form II undergoes polymorphic transformation on prolonged storage and finally converts to more stable form I. Therefore, it is not
the preferred form for development in the pharmaceutical industry.
In the case of metoprolol tartrate, the metastable form I has lower porosity and lesser density and crystal strength compared to
the stable form II. As a result, the metastable form I yields a stronger tablet at low pressure compared to form II and follows
Summers’ rule.170
Bansal and coworkers reported compressibility, tabletability, and compactibility (CTC) profiles of three different polymorphic
systems, namely, ranitidine hydrochloride171 (form I and form II), indomethacin172 (a and g forms), and clopidogrel bisulfate173
(form I and form II), to study the role of crystal packing in governing material properties. In the case of clopidogrel bisulfate, they
exhibit a counterintuitive observation as the high-density form I is less stable compared with form II (stable form). Molecular
packing of the two polymorphs governs the compaction behavior. Close cluster packing of molecules in form I offers a rigid struc-
ture with poor compressibility and hence resists deformation under compaction pressure. However, the high bond strength of form
I results in superior compactibility and tabletability compared with the stable form II of clopidogrel bisulfate. The polymorphic
indomethacin case showed that the g form (thermodynamic form) contains crystallographic slip planes resulting higher compress-
ibility and deformation behavior; however, close molecular packing and higher true density resulted in greater compactibility and
tabletability of the a form (metastable polymorph). A similar result has been observed in the case of ranitidine hydrochloride
system, where the polymorph I having lesser active slip planes compared to form II (lower true density) shows greater tabletability
at a given compaction pressure by virtue of its greater molecular bond strength.
Based on the results discussed earlier, the mechanical properties of a material are not predictable without looking into the crystal
packing and hydrogen bond interactions. Although mechanical properties of all possible polymorphic forms need to be studied
extensively, better tableting properties of a metastable polymorph do not necessarily suggest processing and formulation develop-
ment. The use of an excipient is preferred to overcome mechanical deficits of a stable polymorph rather than developing a metastable
form because of its better mechanical properties as there is always a probability of phase transition for a metastable form.
5.13.4 Computational Methods of Polymorph Prediction and Characterization

5.13.4.1 CSP and CCDC Blind Tests
Computational methods for CSP have been indispensable in the study of polymorphism phenomenon. The main objectives of CSP
are the correct prediction of space group, lattice parameters, and the positional coordinates of atoms for all possible polymorphs of
a compound. A reliable CSP method is also desired for obtaining the correct stability order of polymorphs and their properties so
that structure property relationships can be established. CSP is also found helpful in the characterization of crystal structures from
powder X-ray diffraction and transmission electron microscopy (TEM) data and their validation. Theoretically, there are numerous
crystal structures possible for a given compound. Ascertaining the most probable crystal structures (polymorphs) among these
possibilities is a daunting task and is still a challenge for current CSP approaches. Crystal structure prediction also tries to address
a very fundamental question pertaining to crystallization, that is, how molecules recognize themselves to form a crystal. Due to
inherent complexity, the progression of a molecule to crystal is considered an emergent phenomenon.174,175 The structural infor-
mation of all the possible endpoints (crystal forms) of a crystallization reaction obtained through CSP can be valuable for the iden-
tification of plausible nucleation pathways.176
There are two major issues of concern to the CSP-based screening of polymorphs. First is the availability of an exhaustive crystal
sampling method that can predict all possible polymorphic forms of a drug leaving no future surprises. However, the presence of
a large number of rotatable bonds that is often the case for drugs and the possibility of existence of high Z0 forms make this an
extremely challenging task. Advancements in the crystal structure sampling approaches, especially based on the random search
methods such as Monte Carlo-simulated annealing, have been successful in solving this problem to a large extent. However, in

the past few years, the scope of CSP application has been further widened by the inclusion of other possible crystal forms for
compounds that includes solvates, salts, and cocrystals. These multicomponent crystal forms pose additional challenges to CSP
due to increased crystal search space (not discussed here). The second major issue of concern is the development of a reliable
CSP method for computing the lattice energies of predicted polymorphs with sufficient accuracy so that their relative stabilities
can be obtained unambiguously. Often, the lattice energy differences for polymorphs are found to be less than 1 kJ mol 1. The
development of a reliable method for the determination of intermolecular interaction energies is one of the key aspects of any
CSP study. The lattice energies for predicted crystals are generally obtained using a force field or density functional theory (DFT)
methods. The lattice energy of a molecular crystal is given by
Ecell
Elattice ¼ Egas
Z
where Ecell is the total energy of a unit cell, Z is the total number of molecules in the unit cell, and Egas is the total energy of the
molecule in the gas phase.
CSP blind tests organized by Cambridge Crystallographic Data Centre (CCDC) have been playing a pivotal role in monitoring
the progress in this field. Since 1999, six CSP blind tests (CSP1999,177 CSP2001,178 CSP2004,179 CSP2007,179 CSP2010,180 and
CSP2014181) have been organized. The most recent blind test CSP2014 concluded recently in August 2015. In these years, several
crystal structure prediction approaches have been developed and tested that reflect the advancement in computational methods for
studying intermolecular interactions available at that time. The use of force fields in CSP was very popular in earlier times during the
first three blind tests. Several force field types and charge models were tested during this period for CSP, but all were unsuccessful in
providing a reliable solution to the problem. Further improvements in force field methods with the inclusion of an anisotropic
multipole electrostatic model, incorporation of polarization/induction effects into computations, and improved treatments of
intramolecular flexibility have been considered. However, these methods have failed to achieve the desired accuracy for the predic-
tion of polymorphic forms of a compound. A major problem with these methods was the inaccuracies involved in the treatment of
the dispersion energy component, which plays an important role in determining the stability of molecular crystals. However, these
methods are still popular for crystal structure generation and initial optimization as it helps in reducing computational efforts.182
The CSP2007 and CSP2010 saw major success in structure prediction with the use of hybrid DFT-D method developed by Neu-
mann’s group.183
The wave function and DFT-based approaches are considered better in terms of accuracy but are computationally very expensive.
The periodic DFT methods have become more popular as they are computationally less expensive than wave function-based
methods. However, DFT methods also exhibit problems in the treatment of dispersion interactions leading to discrepancies in
lattice energy computations. Several new GGA (generalized gradient approximation) and meta-GGA exchange–correlation func-
tionals have been developed in the past few years to improve the accuracy of DFT methods.184,185 Besides this, a computationally
less expensive empirical dispersion correction has also been suggested to improve the accuracy of DFT methods and is typically of
the form given in the succeeding text:
1XN C6
Edisp ¼ f Rij 6
2 ij damp Rij
where C6 is the dispersion coefficient and Rij is the interatomic distance. fdamp is the damping function used to correct the long-range
dispersion contributions. The incorporation of these cost-effective empirical dispersion correction terms such as Grimme’s DFT-
D186 has led to significant improvement in the last two CSP blind tests (CSP2007 and CSP2010).182 However, these hybrid
DFT-D method-based CSP approaches have not been found sufficient to discriminate between very low-energy structures.
The dispersion interactions include significant contributions from many-body interactions between the instantaneous dipoles
and multipoles of atoms.187 These many-body terms are highly environment dependent and cannot be accounted for through
a simplified pairwise dispersion energy term. Besides these, nonempirical DFT models for dispersion energy correction are also
being developed but are computationally more expensive.188
5.13.4.2 Many-Body Dispersion Approaches

The inclusion of a standard C6/R6 pairwise additive expression to account for the dispersion energy has shown a significant improve-
ment in the accuracy with DFT-D methods. However, the neglect of higher order many-body dispersion (MBD) terms beyond the
pairwise term can still lead to significant errors in computing lattice energies as they typically account for 5–10% of the lattice
energy. In the many-body formalism, the total lattice energy can be decomposed into contributions from monomer, two-body
(DEij), three-body (DEijk), etc. interaction terms. The contributions from higher many-body terms beyond two-body are generally
neglected in computations. However, these terms become quite important in the computing of the relative stabilities of poly-
morphs, especially when a sub kJ accuracy is desired:
E0K
latt ¼ DEi þ DEij þ DEijk þ /
The use of fragment-based approaches had also been suggested by many researchers for obtaining accurate lattice energies of
molecular crystals from popular electronic structure methods189 such as the second order Møller–Plesset perturbation theory

(MP2), which is a popular method for obtaining dispersion energies for molecular systems. A fragment-based hybrid many-body
interaction model (HMBI) had been proposed by Beran and coworkers to extend the applications of MP2 to infinite periodic
systems.190 Lattice energies for many molecular crystals have been predicted by this method within 1–2 kJ mol 1 of experimental
values. The HMBI approach uses quantum mechanical methods for the computation of one-body (molecular energy components)
and short-range two-body terms (pairwise interactions between molecules). The long-range two-body, three-body, and higher
“many-body” terms are obtained using a classical molecular mechanics (MM) polarizable force field method:
EHMBI
latt ¼ EQM QM MM MM
one body þ Eshort range two body þ Elong range two body þ Emanybody
The relative stabilities of the two aspirin forms (form I was found to be 0.0–0.1 kJ mol 1 more stable than form II) were ob-
tained correctly using this approach and corroborate with the accidental degeneracy hypothesis proposed for occurrence of inter-
growth of two polymorphs found in experiments.191
Tkatchenko and coworkers have developed a new (DFT þ MBD) method to account for nonadditive many-body dispersion
contributions.192,193 The inclusion of higher order many-body dispersion terms and zero-point vibrational energy terms leads to
accurate free-energy differences between the polymorphs. In general, all crystal lattice energy computations are performed at 0 K,
which do not include contributions from zero-point vibrational energy (ZPE) and thermal and entropic terms. The lattice energy
can be related to the sublimation enthalpy (DHsub) by the following thermodynamic equation:
ð
298K
298K

DHsub ¼ E0K 0/298K
latt þ EZPE;gas EZPE;crystal þ DHtrans þ DCp ðT ÞdT
0
where DCp is change in heat capacity, DHtrans corresponds to the enthalpy of transformation, and EZPE is the zero-point vibrational
energy term. Considering the rigid rotor and harmonic approximations and ideal-gas limits, this equation can be further reduced to
298K
DHsub ¼ E0K
latt þ DEvib þ 4RT
where DEvib is the total (thermal and zero-point) vibrational energy difference between the gas and crystal and can be calculated
form DFT phonon calculations:
0 0 11
X X Zup;q
Evib ðT Þ ¼ @ @ þ
Zu p;q AA
q p 2 exp kb Tp;q 1
Zu
where up,q is the pth phonon frequency at wave vector q. The first part of the equation corresponds to ZPE, and the second part
accounts for thermal corrections computed based on the Plank distribution. This method was found to be successful in predicting
the correct stability order for the polymorphic forms of glycine, oxalic acid, and tetrolic acid within experimental error.194 Recent
CSP blind test results also show success in the correct prediction of the stability order of predicted structures using these methods.195
5.13.4.3 Crystal Structure and Energy Landscape

The idea of a landscape is very important both in the context of CSP and for the understanding of crystallization phenomenon. A
crystal energy landscape study is aimed at obtaining the relative stabilities of all thermodynamically feasible crystal structures (poly-
morphs) of a reference compound through CSP to complement experimental screening of polymorphs.196,197 The idea of a crystal
structure landscape on the other hand provides a much broader picture of possible crystallization events as it includes polymorphs,
pseudopolymorphs, solvates, and, under certain conditions, also the other multicomponent crystal forms (salts and cocrystals) of
the reference molecule.176,198 Information about the structural landscape of a compound can be obtained either by a high-
throughput crystallization or crystal structure prediction study or sometimes using both methods. In special cases, the information
about the higher energy structural endpoints of the crystallization landscape can be obtained through a study of the derivatives of
a reference molecule. An excellent example of this is the structural landscape study of benzoic acid and its cocrystals obtained
through the study of fluoro-substituted analogues.199,200 The ideas of crystal energy landscape and crystal structure landscape
are both aimed at the sampling of crystalline phase space of a compound. However, it is to be noted that none of these landscape
studies provides information on the phase transformations and interconversion barriers to enable proper energy profiling of the
lattice energy hypersurface. These phase transformations may sometime involve a large structural rearrangement that are feasibly
only through a liquid state.
5.13.5 Regulatory and Patentability Aspects of Drug Polymorphs

5.13.5.1 Drug Polymorphs and Regulatory Approval of Generic Variants
Identification and characterization of all the polymorphic forms of a drug are very important from the regulatory point of view as
polymorphs may differ drastically in their physicochemical properties. Recent developments in experimental screening approaches
and computational methods of crystal structure prediction appear quite promising for the anticipation of polymorphism in drugs.

However, a prior prediction of all possible polymorphic forms of a drug even by computational means is still a challenge. In many
instances, a metastable polymorph of the drug may appear first during the manufacturing and may convert to a more stable form
during the course of time with a change in environmental conditions (temperature, pressure, and humidity) during processing,
storage, or transport. A classic example of this is the late appearance (after 18 months) of a more stable, poorly soluble polymorph
of the HIV drug ritonavir by the US pharmaceutical firm Abbott Laboratories.21 The poor solubility of this polymorph leads to
severe bioavailability issues due to which Abbott was forced to withdraw the drug from market causing a huge loss. The ritonavir
story has led the US Food and Drug Administration (FDA) and all pharmaceutical companies to seriously consider polymorph
screening for all new drug candidates at earlier stages. Since polymorphs exhibit different physicochemical properties, they are
also considered patentable provided they show improved properties over the known form of the drug.
Generally, if the solid form screening experiments reveal the presence of new polymorphs for a drug, the innovating drug
company tries to seek a polymorph patent based on some favorable property as it helps in extending the patent life of the drug
and to delay the entry of generic pharmaceutical companies. Both polymorphs and pseudopolymorphs of drugs are considered
the same under the term polymorphism defined in the International Conference on Harmonization (ICH) guideline Q6A. FDA
approval of all new drug applications (NDAs) from innovator companies requires stringent regulatory review to prove the drug’s
efficacy and safety prior to the approval. For a drug with multiple polymorphs, the innovator company can choose to develop one
polymorph initially and can develop the other polymorph(s) later to extend the life of the drug further. These secondary patents are
sometimes considered part of an innovator company’s “evergreening” strategies to retain market exclusivity.201 On the expiry of
a patent, the FDA allows a generic drug company to file an abbreviated new drug application (ANDA) for a previously approved
FDA drug under the Hatch-Waxman Act of the United States. According to this act, generic companies are no longer required to
repeat the safety and efficacy testing as required for a new drug, provided they prove bioequivalence of the active ingredient in
the ANDA to the approved patented drug by FDA also called as the reference listed drug (RLD, listed in the FDA Orange Book),
that is, the active ingredient, dosage form, and strength in the generic variant must be the same as the RLD drug. According to
the FDA standard for bioequivalence, the generic drug product should show absorption in the range of 80–125% to that of RLD
brand product. The 2007 FDA guidance considers different polymorphic forms of the active ingredient in the RLD as the same
for the ANDA filing. Hence, if the innovator company holds a patent for a polymorphic form of a drug, it can further delay the entry
of a generic company. Other crystalline forms of drugs such as solvates and hydrates are also considered as polymorphs for the
approval of ANDAs. The Hatch-Waxman Act allows the innovator to file a lawsuit against a generic company for patent infringement
in such cases. In order to streamline generic drug approvals and patent litigation-related issues, the ANDA filing from a generic
company in such cases is required to submit a “paragraph IV certification” to claim that all the RLD patents from the innovator
company are invalid or unenforceable or will not be infringed by the generic company’s proposed generic product. The issues
related to purity of polymorphs of a drug and patent invalidity claims have led to many litigations between the innovator and
generic drug companies. Some of these patent cases that are of relevance to drug polymorphism are discussed in the succeeding text.
5.13.5.2 Ranitidine Hydrochloride (Glaxo vs Novopharm)

Glaxo (now GlaxoSmithKline) was granted the US patent in 1978 (US patent 4,128,658) for the antiulcer drug ranitidine hydro-
chloride (Zantac) form I. Two years later, they discovered a second polymorph, which exhibited better manufacturability character-
istics as it showed improved filtration and drying properties. Glaxo was granted a second patent (US patent 4, 521,431) in 1985 for
the new polymorphic form II on this basis. The expiry of the ranitidine hydrochloride form I patent in 1995 opened the market for
the entry of generic manufacturers to sell a generic version of form I of the drug. However, the existing Glaxo patent for form II posed
difficulties for the FDA approval for ANDA filing from generic pharmaceutical companies as they were forced to ensure that the
generic variant of Zantac (form I) must be free from contamination with form II to avoid patent infringement. Novopharm
(now Teva Canada) filed an ANDA with the FDA to market form II of ranitidine hydrochloride claiming that the method given
from the 1978 patent exclusively gives form II not form I and hence Glaxo’s second patent for form II was invalid. Glaxo filed
a patent infringement case against Novopharm and was successful in proving that form I can be exclusively obtained from the
method given in the first patent. The litigation became more interesting when Novopharm filed another ANDA this time for
form I. This was challenged again by Glaxo on the basis that the Novopharm’s generic variant of form I contained small quantities
of form II and hence could not be granted as the form II patent was still valid. However, the court did not find Glaxo’s argument
satisfactory (form II contamination was < 1% and thus could not be considered as the basis of improvement of the drug property as
claimed in the form II patent) and allowed Novopharm to market form I in 1997. This case demonstrated the importance of phase
purity and characterization techniques for patentability.
5.13.5.3 Paroxetine Hydrochloride (SmithKline Beecham vs Apotex)

Antidepressant drug paroxetine hydrochloride (Paxil and Seroxat) was discovered by a Danish company, Ferrosan, in 1975 (US
patent 4,007,196 published in 1977) and was transferred to Beecham pharmaceuticals (which later became SmithKline Beecham,
now GlaxoSmithKline) in 1980. A hemihydrate form of paroxetine hydrochloride was also discovered by SmithKline Beecham
(SKB) in 1984 (US patent 4,721,723 published in 1988) and was approved by the FDA as Paxil in 1992. The initial ’196 patent
of paroxetine hydrochloride (anhydrate form) expired in 1992. Apotex Corporation filed an ANDA for a generic version of parox-
etine hydrochloride in 1998. SKB filed a patent infringement lawsuit against Apotex claiming the presence of the hemihydrate form

in their generic variant of the paroxetine hydrochloride anhydrate, which converts to the hemihydrate form gradually with time. The
final US federal court ruling in 2004 came in favor of Apotex considering the fact that the generic version does not contain commer-
cially significant amounts of hemihydrate to claim infringement of the SKB ’723 patent.202
This case highlights important scientific issues of polymorphism and pseudopolymorphism equivalence and phase transforma-
tions in drug. Most importantly, in the aforementioned cases, the innovator company was successful in delaying the generic entry
through new form patents and retained their control over the drug market for a valuable period of time.
5.13.5.4 Amlodipine (Pfizer vs Apotex)

Amlodipine, an antihypertensive and antiischemic drug, was discovered by Pfizer and was patent filed in 1982 (US patent
4,572,909). A maleate salt of amlodipine was initially chosen by Pfizer for drug development. However, due to poor stability
and manufacturability (as it was found too sticky), it was not taken further. A besylate salt of amlodipine was later developed (Nor-
vasc, launched in 1990) to overcome these issues, and a patent was filed in 1986 citing its favorable solubility, stability, nonhydro-
scopicity, and manufacturability properties (US patent 4,879,303) valid until the year 2007. Apotex along with other generic
companies (Mylan and Teva) filed an ANDA to the FDA to market the generic version in 2005 (on expiry of the ’909 patent)
with paragraph IV certification that the ’303 patent of amlodipine besylate salt was invalid and unenforceable as the besylate
salt was obvious from the previously disclosed maleate salt. Pfizer filed for infringement of the ’303 patent against Apotex to
stay FDA approval of its generic variant. Pfizer won the initial lawsuits in the lower courts but was finally turned down by the
US federal court invalidating the ’303 patent for the besylate salt as obvious and routine in the pharmaceutical industry and allowed
the entry of generic companies a few months before the expiry of ’303 patent.
Patent laws for polymorphs and other crystal forms of a drug vary from one country to another. In 1995, the World Trade Orga-
nization proposed unification of patent laws applicable in member countries by setting a minimum standard for intellectual prop-
erty rights protection by asking them to join the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS).
However, developing countries were given an additional 10 year extension until 2005 to transform their patent laws accordingly.
The member countries were given additional flexibility to allow or deny patent approval in specific cases such as those involving
human life or health emergencies. Among the TRIPS countries, India adopts a very clear and more stringent policy for patentability
of new salts or polymorphs of drugs. These forms were not considered patentable previously in India before the 2005 amendments
to the Indian Patent Act. The new patent law that came into effect after the 2005 amendment (under the obligation of TRIPS)
allowed patents for new polymorphic forms of a drug provided it results in significant improvement in the therapeutic efficacy
of the drug. Patentability of polymorphs merely based on improved physicochemical properties, that is, thermodynamic stability,
hygroscopicity, and manufacturability characteristics, was not considered under section 3(d) of the 2005 amendment.203 Section
3(d) of the Indian Patent Act clearly states that “mere discovery of a new form of a known substance which does not result in
the enhancement of the known efficacy of that substance is not an invention.” This section was introduced by taking account of
the secondary patents filed by pharmaceutical innovator companies under their “evergreening” strategies and to provide access
to life-saving drugs to the citizens of the country. The Supreme Court of India’s judgment on the Novartis anticancer drug Gleevec
is a landmark in this regard and has been applauded worldwide.204
5.13.5.5 Imatinib Mesylate (Novartis vs Government of India)

Imatinib is an anticancer drug marketed by Novartis as Gleevec (also Glivec). The freebase form of imatinib was patented by
Novartis in 1996 (US patent 5,521,184) popularly known as the Zimmermann patent describing synthesis of other N-phenyl-2-
pyrimidine-amine derivatives. The Zimmermann patent also mentioned a list of pharmaceutically acceptable salts including mesy-
late for these N-phenyl-2-pyrimidine-amine derivatives. A second polymorph of imatinib (b-crystalline form) was subsequently
discovered in 1997 and granted a patent in 2005 based on advantageous properties (US patent no. 6,894,051) and was approved
by the FDA in 2002 as Gleevec. In 1998, Novartis filed a patent application (1602/MAS/1998) for the b-crystalline form of imatinib
mesylate in India, which was kept in a mailbox until 2005 (Indian Patent Act become TRIPS compliant). Novartis also applied for
exclusive marketing rights (EMR) for imatinib mesylate (Glivec) in India until its application for the b-crystalline form was pro-
cessed and was granted an EMR. After the 2005 amendment, various generic companies and NGOs filed pregrant opposition against
Novartis’ patent for the b-crystalline form claiming it not novel as it did not involve an inventive step and therefore did not meet
patentability criteria under section 3(d). Novartis submitted expert reports claiming that the b-crystalline form is more soluble and
results in a 30% increase in bioavailability with respect to its freebase form. However, the opponents argued the comparison for
enhanced efficacy should be drawn between the a- and b-crystalline forms of imatinib mesylate and not with its freebase. The patent
controller refused to grant the b-crystalline form patent to Novartis. Novartis then filed a writ petition against the Government of
India at the Madras High Court against this decision also challenging the validity of section 3(d). The battle was taken further by
Novartis to the Supreme Court of India. In the Gleevec case, the Supreme Court of India’s interpretation for “efficacy” under section
3(d) was quite strong in rejecting Novartis claims. The Novartis patent application for the b-crystalline form was rejected in June
2009 by intellectual property appellate board (IPAB) stating the invention is not worthy of a patent for not satisfying the require-
ment of section 3(d).
The Supreme Court of India’s landmark ruling in the case of life-saving drugs such as Gleevec has started to show impact on the
patentability laws being drafted in various other developing countries.205 It serves as an example for the obligation of the

government to the people of its country by protecting issues pertaining to human welfare of its citizen permissible in the TRIPS
framework. Influenced by section 3(d) of the Indian Patent Act, the Brazilian Patent and Trademark Office (BRPTO) has sought
public opinions on the draft guidelines for patentable subject matter and patentability requirements in March 2015.206
Crystal polymorphism in drugs remains a central topic of research to academia and industry. We are well aware of the benefits
and consequences of overlooking polymorphism phenomena in drugs. However, the anticipation of polymorphs and development
of advanced technologies for their screening and control are still a problem. The emergences of complex cases like intergrowth poly-
morphs are also posing new challenges for current characterization techniques. Modern methods of polymorph screening such as
polymer-induced heteronucleation, use of supercritical fluids (SCF), screw extrusion method (HTE and HME), and high-throughput
crystallization methods appear very promising as they open up new avenues for obtaining previously inaccessible polymorphs of
a compound. The importance of CSP in the study of polymorphism cannot be undermined and must be considered complementary
to experimental methods. Future studies of polymorphism will benefit most from a collaborative effort from advances in compu-
tational and experimental techniques so that all possible polymorphs of a compound can be predicted and should also be obtained
experimentally from any of these advanced screening techniques.
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Crystal Polymorphism in Pharmaceutical Science

Chapter · June 2017

Ranjit Thakuria Tejender S. Thakur

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From Thakuria, R.; Thakur, T. S. (2017) Crystal Polymorphism in Pharmaceutical Science.

5.13 Crystal Polymorphism in Pharmaceutical Science

5.13.1 Introduction 283

Comprehensive Supramolecular Chemistry II, Volume 5 http://dx.doi.org/10.1016/B978-0-12-409547-2.12570-3 283

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Table 1 Physical properties that differ among various solid phases

Packing properties Kinetic properties

5.13.1.2 Deﬁnition and General Classiﬁcation/Types

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.1.3 Pseudopolymorphism and Polymorphism in Other Multicomponent Systems

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.1.4 Ostwald’s Rule of Stages, Concomitancy, Intergrowth, and High Z 0 Polymorphs

5.13.2 Experimental Approaches for Polymorph Screening and Characterization

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.2.2 Characterization of Polymorphic Forms

5.13.2.2.1 X-ray diffraction

5.13.2.2.2 Thermal methods

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.2.2.3 Spectroscopic methods

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.2.2.4 AFM, nanoindentation, and TEM methods

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.3 Impact of Polymorphism on the Physicochemical Properties of Drugs

5.13.3.2 Dissolution Rate and Bioavailability

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309

2000, 193, 137–146. Copyright 2000 Elsevier.

5.13.3.4 Chemical Stability

Figure 18 Photodegradation products of carbamazepine.

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Figure 19 Reaction between indomethacin and ammonia.

5.13.3.5 Mechanical Properties

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.4 Computational Methods of Polymorph Prediction and Characterization

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.4.2 Many-Body Dispersion Approaches

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.4.3 Crystal Structure and Energy Landscape

5.13.5 Regulatory and Patentability Aspects of Drug Polymorphs

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.5.2 Ranitidine Hydrochloride (Glaxo vs Novopharm)

5.13.5.3 Paroxetine Hydrochloride (SmithKline Beecham vs Apotex)

Comprehensive Supramolecular Chemistry II, 2017, 283–309

5.13.5.4 Amlodipine (Pﬁzer vs Apotex)

5.13.5.5 Imatinib Mesylate (Novartis vs Government of India)

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309

Comprehensive Supramolecular Chemistry II, 2017, 283–309