INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/19697/5/05_chapter...
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1
CHAPTER – I
INTRODUCTION
1.1. Chemical Crystallography
The knowledge of accurate molecular structure is a prerequisite for drug
design and structure-based functional studies to aid the development of effective
therapeutic agents and drugs. Crystallography is the experimental science of the
arrangement of atoms in solids. It provides a reliable answer to many structure-related
questions from global fields to atomic details of bondings. Crystallographic methods
depend on the analysis of the diffraction patterns of a sample targeted by a beam of X-
rays, neutrons, or electrons. These three types of radiations interact with the specimen
in different ways. Because of these different forms of interactions, the three types of
radiations are suitable for different crystallographic studies. However, X-rays are the
most commonly used in crystallographic studies.
Chemical crystallography is expected to pave paths into nano sciences,
reaction pathways and also, above all, make significant contributions to biological
science1a,1b
.
1.2. Supramolecular chemistry
Supramolecular chemistry is relatively a new field of chemistry which focuses
literally on going “beyond” molecular chemistry2. D. J. Cram, J. M. Lehn, and C. J.
Pedersen recognized the importance of supramolecular chemistry and for their work
in this area they were awarded Nobel Prize for Chemistry in 1987. Unlike the organic
synthesis which utilizes covalent bonds to synthesize a desired molecule,
supramolecular chemistry utilizes far-weaker and reversible non-covalent interactions
such as hydrogen bonding, metal coordination, hydrophobic forces, van der Walls
2
forces, π-π interactions and sometimes electrostatic effects to assemble molecules into
multimolecular complexes. Among these different types of non-covalent interactions,
the hydrogen bonding plays a very important role in supramolecular organization.
Various fields that are classified under supramolecular chemistry include
molecular self-assembly, molecular recognition, host-guest chemistry, mechanically-
interlocked molecular architectures, and dynamic covalent chemistry3. It is important
for the development of new pharmaceutical therapies by understanding the
interactions at a drug binding site. In addition, supramolecular systems have been
designed to disrupt protein-protein interactions that are important for cellular
function. It also has applications in green chemistry.
1.2.1. Application of Supramolecules
Molecular devices are functional materials that are structurally precise down
to the molecular level and are constructed using the concepts of supramolecular
chemistry. Super molecules capable of electron conduction and electrical switches5
(molecular electronic devices), supermolecules that can be used for information
processing and calculations (molecular computer) and supermolecules that move,
rotate and catch targets (molecular machines) are introduced as examples of
molecular devices6. Well-defined molecular assembles provide useful devices for
direction controlled information transfer. These examples suggest that supramolecular
chemistry will be the main tool used in the development of biotechnology and
nanotechnology which are predicted to revolutionize our life styles and economics in
the near future7.
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1.3. Hydrogen bonding
The hydrogen bond was discovered almost 100 years ago8, but still it is a topic
of vital scientific research. The reason for this long-lasting interest lies in the eminent
importance of hydrogen bonds for the structure, function, and dynamics of a vast
number of chemical systems which range from inorganic to biological chemistry. The
diverse scientific branches involved are mineralogy, material science, general
inorganic and organic chemistry, molecular medicine and pharmacy4.9.10
The interest in this subject is rapidly developing as shown in the Fig. 1.1. The
number of references in chemical abstracts under the heading ‘The Hydrogen Bond’
has increased progressively. It is reasonable to predict that a paper on hydrogen
bonding is now being published every half an hour of the working day, somewhere in
the world11
.
Figure 1.1 Number of papers abstracted by Chemical Abstracts under the subject
index with “Hydrogen Bonding”
6000 -
5000 -
4000 -
3000 -
2000 -
1000 -
1957- 1962- 1967- 1972- 1977- 1982-
1961 1966 1971 1976 1981 1986
Pu
bli
cati
on
s
Years
4
Studies carried out in the period 1939-1953 showed strong evidence that the
principal cohesive forces between the subunits of biological structures were hydrogen
bonds. These were recognized as stronger than van der Waals forces and more
directional leading to compounds with high melting points and generally harder
crystals. The significance of hydrogen bonding in biological structure was realized by
the two major discoveries, the α-helix and β-pleated sheet structure of protein
architecture in 1951 and the Watson-Crick base-pairing in the DNA double helix in
1953. All subsequent structural research on proteins and nucleic acids has reinforced
the concept that although hydrogen bonds are weak interactions, they are the most
important atomic interactions, determining the three-dimensional folding of biological
macromolecules12
. Life would be impossible without hydrogen bond!
Hydrogen bond is a weak electrostatic chemical bond which forms between
covalently bonded hydrogen atoms and a strongly electronegative atom with a lone
pair of electrons. Because of the strong and highly directional nature of hydrogen
bond, it has been described as the ‘master key interaction’ in the areas of
supramolecular chemistry, material science and biological recognition13-17
. Hydrogen
bonding occurs between a proton donor group D-H and a proton acceptor group A.
The D-H…A interaction is called a ‘hydrogen bond’ (bond energy 1-40 Kcals/mol).
George Jeffrey12
has an in-depth study of hydrogen bonds and classified them
into three general categories as (i) very strong, (ii) moderate/strong, and (iii) weak,
according to the energy of interaction. General properties of these three types of
hydrogen bonds are tabulated in Table 1.1. These three divisions are mainly for our
convenience, since there is very much a ‘continuum of the hydrogen bonds’ with the
weakest strong bond being of comparable energy to the strongest medium bond and
so on. According to the suggestion made by Hamilton and Ibers, the distance of the
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atoms, which is less than the sums of their van der Waals radii, is a sufficient, but not
a necessary condition for hydrogen bond formation18
.
Table 1.1 Properties of Hydrogen Bonds
Properties Very Strong Moderate Weak Bond
Bond Energy((kcal/mol) 15−40 4−15 <4
Examples
[F─H…F]-
[N─ H…N]+
[P─ OH…O=P]
O─H…O=C
N─H…O=C
O─H…O─H
C─H…O
O─H…π
Os─H…O
Relative frequency shift
in IR >25% 5-25% <5%
Bond lengths H…A ≈ X─H H…A > X─H H…A >> X─H
Lengthening of X─H (Ǻ) 0.05−0.2 0.01−0.05 ≤ 0.01
D (X…A) range (Ǻ) 2.2−2.5 1.5−2.2 3.0−4.0
d (H…A) range (Ǻ) 1.2−1.5 1.5−2.2 2.0−3.0
Bonds shorter than
vander Waals radii 100%
Almost 100%
30−80%
θ(X─H…A) range (Ǻ) 175−180 130−180 90−180
kT (at room
temperature) >25 7−25 <7
Effect on crystal
packing Strong Distinctive Variable
Utility in crystal
engineering Unknown Useful Partly useful
Covalency Pronounced Weak Vanishing
Electrostatics Significant Dominant Moderate
As hydrogen bonds are of long range interactions, a group X–H can be bonded
to more than one acceptor (A) at the same time. If there are two or more acceptors in a
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hydrogen bond then that is called a bifurcated or trifurcated respectively, hydrogen
bond (Figure 1.2).
Nearly linear bifurcated acceptor bifurcated donor trifurcated donor
Figure 1.2 Different hydrogen bond patterns
In many supramolecular self assembling structures, the individual components
are held together by arrays of double [for instance AT (Adenine-Thymine) base pair;
Figure 1.3a], triple [for instance GC (Guanine-Cytosine) base pair; Figure 1.3b]
quadruple19
and quintuple20
hydrogen bonds. Whitesides et al21-24
extensively
investigated the hydrogen-bonded adduct of melamine and cyanuric acid forming
rosettes (cyclic hexamer) and tape motifs having multiple hydrogen bond network
(Figure 1.4).
Figure 1.3 Double and triple hydrogen bonds in DNA base pairs
(a) AT pair, (b) GC pair.
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Figure 1.4 Rosette and tape motifs in the solid state structure of melamine: cyanuric
acid
Hydrogen bonding is probably the most widely used interaction to generate
supramolecularly organized organic systems with a variety of novel structural
features25-29
. Such supramolecularly organized organic solids show unique chemical
and physical30-32
properties including porosity33-35
. Hydrogen bonding has been
effectively used to predict and design supramolecular assemblies in one and two
dimension36-41
. Hydrogen bonded systems generated from organic cations and anions
are of special interest since they would be expected to show stronger hydrogen bonds
than neutral molecules and enable the use of simple acid-base chemistry to tune donor
and acceptor properties of the counterions.
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1.3.1. Graph Set Analysis
Etter, Bernstein, and coworkers have introduced a language based upon graph-
theory for describing and analyzing hydrogen bond networks in three-dimensional
solids42-44
. Perhaps, the most remarkable feature of the graph set approach to analysis
of hydrogen bond patterns is the fact that even complicated networks can be
simplified to combinations of four simple patterns. Each pattern specified by a
designator: chains (C), rings (R), intramolecular hydrogen-bonded patterns (S), and
other finite patterns (D).
The graph set descriptor is given as
Ga
d (n)
Where G = descriptor referring to one of the four patterns of hydrogen bonding.
a = hydrogen bond acceptor
b = hydrogen bond donor
n = degree (number of atoms) of the pattern.
These four patterns and their descriptors are best illustrated by the following
examples figure 1.5 and 1.6
Figure 1.5 Some examples of the four basic descriptors used to define hydrogen bond
patterns
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Figure 1.6 Graph set assignments for the binary level α-glycine
A structure containing only one type of hydrogen bond is referred to as motif
and will have one or more graph set descriptors associated with it. In more complex
cases, where there is more than one motif in the structure, it is possible to assign
graph set descriptors for each motif individually as if the others were not present.
Such descriptors are termed as first level graph sets (N1). Second level (N2) and third
level graph sets (N3) are used for structures having two (Figure 1.7) and three types of
motifs respectively.
Figure 1.7 Examples of first (N1) and second level (N2) graph sets
10
Graph set analysis of hydrogen bonding is a useful tool for the diagnosis,
analysis, understanding, and prediction of supramolecular aggregates dominated by
hydrogen bonds. It is very much helpful in distinguishing polymorphs45,46
.
1.4. Crystal Engineering
Crystal engineering is a flourishing field of research in modern chemistry,
practiced by scientists interested in modeling, design, synthesis, and application of
crystalline solids. It is a sub-discipline of supramolecular chemistry, dealing with the
construction of crystalline materials from molecules or ions by the exploitation of
non-covalent interactions10
. These materials might exhibit interesting electrical,
magnetic and optical properties. It is also recognized that it is becoming increasingly
evident that the specificity, directionality, and predictability of intermolecular
hydrogen bonds can be utilized to assemble supramolecular structures of, at the very
least, controlled dimensionality47
. The non-covalent interactions which have been
exploited in this field are hydrogen bonding, π…..π, dipole interactions, ionic bonds,
hydrophobic interactions, London dispersion forces etc.
The term ‘crystal engineering’ was coined by Pepinsky in 1955, but it was
popularized by the work of Schmidt in solid state photochemistry and this is
considered as the beginning era of crystal engineering48
. By his work it was clear that
the chemical and physical properties of the crystalline solids are dependent on the
arrangement of the molecules in the crystal lattice.
Gautam Desiraju, in this context, defined crystal engineering as given below.
“Crystal engineering is the understanding of intermolecular interactions in the context
of crystal packing and in the utilization of such understanding in the design of new
solids with desired physical and chemical properties”.
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What best the chemists can do is to find recurring packing patterns adopted by
certain functional groups and rely on the robustness of such motifs to create new solid
structures. The repetitive units of these small-sized hydrogen-bonded motifs are
supramolecular synthons49
and they hold the key to crystal engineering. The design
of a number of supramolecular architectures, layers, ribbons, rosettes, rods, tubes,
sheets and spheres can be achieved through N-H---O and O-H---O hydrogen bonds.
Further more, the diversity of the physicochemical properties that are associated with
crystal engineered materials can be exploited in many areas as exemplified by co-
crystals, which have relevance to host-guest chemistry50
, Non-Linear Optics (NLO)51
,
organic-conductors52
, photographic materials53
, pharmaceuticals54-57
, and solid state
organic chemistry58
.
1.5. History and Definitions of Co-crystals
Co-crystals belong to the class of compounds which are long known but little
studied. Co-crystals have been the subject of research for the past 165 years. Earlier,
co-crystals were known with different names like molecular compounds59
, organic
molecular compounds60
, addition compounds61
, molecular complexes62
, solid-state
complexes63
or hetromolecular crystals64
. Wholer synthesized the first co-crystal of
quinhydrone (Figure 1.8) in 1844 and several related co-crystals were made from
halogenated quinones59, 65
.
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Figure 1.8 Crystal structure of the triclinic form of quinhydrone
The structural information for the co-crystal was absent until 1960. The
elucidation of DNA structure66,67
through X-ray analysis inspired many people to
synthesize numerous nucleobase complexes in 1950’s and 60’s68-71. The term “co-
crystal” was first coined72 in this context and then it was popularized by Etter
73, one
of the more prolific researchers of the era.
During this time, Hoogstein synthesized the new base pair called “Hoogstein
base pair” (Figure 1.9), a co-crystal formed between 9-methyladenine and 1-
methylthymine70
.
Figure 1.9 Hoogstein base-pair
13
Though the term co-crystal sounds very simple, the definition is often a topic
of debate74, 75
.
Stahly76
defined co-crystal as “a crystalline structure with unique properties
that is made up of two or more components. A component may be an atom, ionic
compound, or molecule”.
The Zaworotko research group77
defines co-crystals as “a multiple component
crystal in which all components (molecule or ion and a molecular co-crystal former)
are solid under ambient conditions when in their pure form”.
Aakeroy and coworkers78
defined co-crystals as (i) compounds constructed
from neutral molecules (ii) structurally homogenous crystalline materials that contain
at least two neutral building blocks with a well-defined stoichiometry and (iii)
compounds made from reactants that are solids at ambient conditions.
Dunitz79
gave a broad definition to co-crystal as ‘a crystal containing two or
more components together’, and thus co-crystal encompasses molecular compounds,
molecular complexes, solvates inclusion compounds, channel compounds, clathrates,
and possibly a few other types of multi-component crystals.
Whatever way people define the term co-crystal, the field of co-crystal is
attaining the heights of excellence and Figure 1.10 reveals the growing interest in the
subject.
Therefore, it is evident that co-crystals play a pivotal role in many industries
such as pharmaceutical, textile, paper, chemical processing, photographic, propellant
and electronic.
14
Figure 1.10 Occurrence of the term “co-crystal” in titles and abstracts of papers
published during 1991–2007.
1.5.1. Synthon Approach to Co-crystal Design
Crystal engineering utilizes an empirical knowledge of the non-covalent forces
that trigger the formation of supramolecular synthons80
, which are subsequently
exploited to form compounds with desired physical and chemical properties.
Supramolecular synthons are the smallest structural units within which is encoded all
the information inherent in the mutual recognition of molecules to yield solid state
super molecules, that is, crystals. The key aspect of crystal engineering is, therefore,
the dissection of a target network into supramolecular synthons. The understanding
of supramolecular synthons, their geometries, and their frequency of occurrence in the
presence of other hydrogen bonding groups is a must for the rational design and
supramolecular synthesis of novel co-crystals. Hydrogen-bonded supramolecular
synthons are commonly used in crystal engineering of co-crystals due to their
relatively high strength, predictability, ubiquity, and directionality81-85
.
15
Acid-acid homosynthons Amide-amide homosynthons
Acid-pyridine heterosynthons Amide-acid heterosynthons
Figure 1.11 Supramolecular homosynthons and heterosynthons in co-crystals
Supramolecular synthons are classified into two categories: supramolecular
homosynthons and supramolecular heterosynthons86
. The supramolecular
homosynthons are formed between the same, self-complementary functional groups
and supramolecular heterosynthons are formed between different but complementary
functional groups. Examples of supramolecular homosynthons include the dimers
formed between carboxylic acids and amides80,87,88
,
whereas supramolecular
heterosynthons include carboxylic acid…amide89-93, hydroxyl…pyridine94-96
and
carboxylic acid…pyridine97-100 (Figure 1.11).
The supramolecular homosynthons usually exist in structures of single-
component compounds. For example, the carboxylic acids exist as dimers, whereas, if
multiple functional groups are present, a supramolecualr heterosynthon is more likely
to be formed, as the formation of heterosynthons wins over the homosynthons
whenever these two are competing each other. When a supramolecular heterosynthon
16
is formed between two functional groups that are located on different molecules, a
multi component is formed.
Co-crystals are ideally suited to study the competition between different
supramolecular heterosynthons81
. In general, co-crystals are formed by
supramolecular heterosynthons rather than supramolecular homosynthons. According
to ‘co-crystal approach’, a co-crystal will be produced only if the favoured
supramolecular heterosynthon is formed between the reacting molecules. Conversely,
a co-crystal is not expected to form if a dominant supramolecular heterosynthon can
occur between the functional groups present in the same component.
Synthons explain molecular recognition when molecules assemble into
supramolecules/co-crystals and illustrate the conceptual similarities between
retrosynthetic phenomenon and supramolecular assembly101
. Synthon-based co-
crystal design has become increasingly important to the synthesis of new co-crystals.
1.5.2. Pharmaceutical Co-crystals
Most of the ‘Active Pharmaceutical Ingredients (APIs)’ are administered in
the solid state as part of an approved dosage type, like tablets, capsules etc as they are
the convenient and compact formats to store a drug. APIs can exist in a variety of
distinct solid forms, where each form may display unique physicochemical properties
such as hygroscopicity, morphology and most importantly solubility.
Physicochemical properties of a solid form depend on the arrangement of molecules
in the crystal lattice102
. The solid form of the drug dictates the properties like stability,
hygroscopicity, dissolution rate, solubility and bioavailability. Figure 1.12 represents
the different ways in which drugs are administered103
.
17
Figure 1.12 Different forms of drugs in which they are administered.
This makes the pharmaceutics to look for a crystal form with the best
properties for therapeutic use and manufacturability. Therefore, whatever form of
drug is selected, it must be amenable to handling and processing and as a drug it must
be effective and safe.
Though co-crystals were discovered in the 19th
century, the pharmaceutical
industry has only been recently attracted towards the potential applications 57,
104-107
of
co-crystals. This is exemplified by the growing number of related publications and
conferences and the number of single crystal structures deposited in the Cambridge
Structural Database System (CSDS).
Pharmaceutical co-crystals are crystalline molecular complexes that contain
therapeutically active molecules. They represent a new paradigm in API formulation
18
that might address important intellectual and physical property issues in the context of
drug development and delivery108
. Properties essential to the bio-availability such as
solubility, physical stability, hygroscopicity, and dissolution rate have been
demonstrated in case of co-crystallization109
. Co-crystal formation does not require an
ionizable center on the pharmaceutical molecule, as in the case for salt formation. In
contrast to the limited number of salt-forming counter ions available to-day, there
exists a relatively large number of biologically non-toxic co-crystallizing molecules
available for use in complexation with pharmaceuticals. These pharmaceuticals
include food ingredients and additives, vitamins, nutrients, pharmaceutical excipients,
biomolecules, and other drug molecules.
Pharmaceutical co-crystallization is potentially attractive for improving the
material properties while leaving an API unaltered. The inherent advantages of
pharmaceutical co-crystallization indicate a significant impact on the development of
future medicines. A pharmaceutical co-crystal might also be used to isolate or purify
an API during manufacturing and the co-crystal former may be discarded before
formulation.
The first application of crystal engineering to generate pharmaceutical co-
crystal was a series of studies by Whitesides et al110-116
with the use of substituted
barbituric acid, including barbital and melamine derivatives and they generated
supramolecular ‘linear tapes’, ‘crinkled tapes’, and ‘rosette’ motifs.
To date, many pharmaceutical co-crystals have been reported in the scientific
and patent literature and most of the co-crystals have been found to exhibit improved
material properties like solubility, stability, bioavailability etc. over the pure API.
Pharmaceutical co-crystals have been described for many drugs such as
19
acetoaminophen, aspirin, ibuprofen, caffeine, cephalexin, fluoxetine, theophylline
sulfadimidine, trimethoprim, paracetamol etc117-133
.
Co-crystallization can also be used for chiral resolution. APIs, which are
obtained only in the amorphous form, may be crystallized as co-crystals. For
example, itraconazole, an extremely water insoluble antifungal drug that is marketed
in the amorphous form has been made into co-crystals with certain 1,4-dicarboxylic
acids. (Figure 1.13)
(a)
(b)
Figure 1.13 Structure of itraconazole: succinic acid co-crystal (a) chemical diagram
(b) crystal packing diagram
20
The applications of concepts of supramolecular synthesis and crystal
engineering to the development of pharmaceutical co-crystals offer many
opportunities for the drug development and delivery. So it would not be an
exaggeration in saying that sooner or later pharmaceutical co-crystals will gain a
broader foothold in drug formulation.
1.5.3. Polymorphism
Polymorphism134-140
is the phenomenon wherein the same chemical compound
exists in different crystal forms. In the initial days of crystal engineering,
polymorphism was not properly understood. Today, it is one of the most exciting
branches of the subject. Polymorphism in multi-component crystal is gaining interest
in the recent times in the context of pharmaceutical co-crystals. Polymorphs have
different stabilities and may spontaneously convert from a metastable form (unstable
form) to the stable form at a particular temperature. In addition, they exhibit different
melting points and solubility which affect the dissolution rate of drug and thereby, its
bioavailability in the body. Co-crystal polymorphs suggest additional options to
modify properties, increase patent protection, and improve marketed formulations.
Aswini Nangia137
schematically represented the polymorphic forms of a rigid
molecule (Figure 1.14).
Figure 1.14 Schematic representation of polymorph I and polymorph II for a rigid
molecule
21
1.5.4. Pharmaceutical Co-crystals as Intellectual Property
Compared to other classes of solid forms, co-crystals possess particular
scientific and regulatory advantages. These advantages are intellectual property issues
which give unique opportunities and challenges to co-crystals. Researchers reported
the importance regarding patents on pharmaceutical co-crystals to the pharmaceutical
industry. The value of co-crystals to the pharmaceutical industry should become
clearer, mainly with respect to several relevant legal and regulatory issues, as products
containing co-crystal technology should enter into the market through pharmaceutical
development pipelines.
A novel polymorph can offer an opportunity in terms of better
physicochemical performance and new product development. Physicochemical
properties of a compound can differ critically from one form to another. Hence
inducing and controlling a specific polymorph are very important in the chemistry of
pharmaceuticals139, 140
, explosives141
, pigments142, 143
etc.
Polymorphism tends to be prominent in molecules that contain multiple,
hydrogen-bonding moieties, thereby forming multiple supramolecular synthons80
,
and/or conformational flexibility136,144,145
as exemplified by ROY146
and in a number
of APIs such as aspirin147
, piracetam148,149
, and virazole150
. In addition, simultaneous
crystallization of polymorphs, known as concomitant polymorphism151
, can occur
under certain conditions.
Polymorphism occurs in single component crystals, salts, and solvates and is
exhibited by most APIs. It is worthy to note that the number of polymorphs of a co-
crystal was more than the number of polymorphs of its parent API.
Two different polymorphic forms of paracetamol are reported by Oswald et
al151
. Carbamazepine-nicotinamide co-crystal and carbamazepine-saccharin co-crystal
22
were found to exist in two polymorphic forms152
. Co-crystal polymorphs of
carbamazepine and isonicotinamide having 1:1 stoichiometry were reported and they
were formed through a solvent-mediated transformation process upon suspending a
dry mixture of the pure crystalline components in ethanol153
. Two polymorphs of a
co-crystal between 2-ethoxybenzamide and saccharin sustained by a carboxamide-
imide heterosynthon involving two N-H---O hydrogen bonds were prepared and
structurally characterized by single crystal X-ray diffraction. The metastable form
alone was formed in the grinding experiment, whereas both polymorphs were reported
by solution crystallization.
Polymorphs are considered important in the pharmaceutical industry in view
of their effectiveness in the drug. For example, out of its four polymorphic forms,
only one form of cortisone is stable in water.
1.6. Crystal Growing and Crystal Quality
The aim is to grow single crystals of suitable size in at least two of the three
dimensions. The size of the crystals can be influenced by a number of factors such as
the solubility of the sample in the chosen solvent, the number of nucleation sites and
time. A solvent should be chosen to facilitate the sample moderately soluble. The
crystal-growing vessel should be clean, because dust provides numerous nucleation
sites and may initiate interfering crystal growth. It is important to avoid disturbance
of the vessel. Vibration or frequent movement tends to lead to poor quality crystals.
The most promising crystals are transparent and sharp-edged with the
preferred dimensions. Acceptable crystals may be produced serendipitously from the
preparative route. Different colours or shapes of crystals may indicate unreacted
23
starting material or by-products. If the crystal is not of sufficient quality, it may be
necessary to use a different crystallization technique.
Producing good quality crystals of a suitable size is the first and most
important step in determining any crystal structure. Crystallization is the process of
arranging atoms or molecules that are in a fluid or solution state into an ordered solid
state. Co-crystallization is a deliberate attempt at bringing together different
molecular species within one periodic crystalline lattice without making or breaking
covalent bonds. Recrystallization and co-crystallization processes (Figure 1.15) are, in
essence, only distinguishable by their intents. The goal of recrystallization is a
homomeric product, whereas the co-crystallization procedure strives for a heteromeric
product. Crystallization process occurs in two steps, nucleation and growth.
Nucleation may occur at a seed crystal. In the absence of seed crystals, it usually
occurs at some particle of dust or at some imperfection in the surrounding vessel.
Crystals grow by the ordered deposition of material from the fluid or solution state to
a surface of the crystal.
Figure 1.15 Schematic representation of recrystallization and
co-crystallization
1.6.1. Crystallization Methods
There are numerous ways to grow crystals. The choice of method depends
greatly upon the physical and chemical properties of the sample. For solution methods
24
of crystallization, the solubility of the sample in various solvent systems must be
explored. If heating methods are selected for growing crystals, the thermal stability
and melting point of the sample should be determined.
1.6.1.1. Evaporation Method
Evaporation is by far one of the easiest methods for crystallizing organic and
organometallic small molecule compounds. The choice of solvent is very important,
because it can greatly influence the mechanism of crystal growth and the solvent may
be incorporated into the crystalline lattice. It is customary to screen a large number of
solvents or solvent mixtures to find the best conditions for crystal growth. The rate of
crystal growth can be slowed either by reducing the rate of evaporation of the solvent
or by cooling the solution. Formation of only a few rosette-shaped masses is an
indication of an insufficient number of nucleation sites. The number of nucleation
sites may be increased either by seeding the solution or by scratching the exposed
surfaces of the glass vessel.
1.6.1.2. Liquid and Vapor Diffusion Methods
Liquid and vapor diffusion methods are often tried when evaporation methods
do not immediately succeed. Both methods require finding two solvents or solvent
mixtures in which the compound is soluble in one system but insoluble in the other.
The two solvent systems should be immiscible or nearly immiscible for liquid
diffusion and should be miscible for vapor diffusion. Crystal growth may be slowed
somewhat by cooling the apparatus. Liquid diffusion usually requires that the less
dense solvent system be carefully layered on top of the more dense system. The
25
sample can be dissolved in either solvent system. Crystals grow at the interface
between the solutions.
When compounds precipitate immediately upon being formed, it is possible to
slow down the reaction and thus grow larger crystals by putting the reactants in
different liquid layers which are separated by a third solvent layer that is not miscible
with either of the layers or with the sample. The top layer should be added very
slowly to assure a minimum of mixing of the layers.
Vapor diffusion is carried out by dissolving a small amount of the sample in a
small vial, then placing this inner vial inside a larger vial that contains a small volume
of a solvent system in which the sample is insoluble. The outer vial is then sealed.
Vapor from the solvent of the outer vial then diffuses into the solution in the inner
vial, causing the compound to grow crystals. The vertical surfaces of the inner vial
should not touch the outer vial to keep the outer solution from rising by capillary
action and filling the inner vial.
1.6.1.3. Thermal Gradient Method
Thermal gradient methods usually produce very high quality crystals. Such
methods include slow cooling of sealed, saturated solutions, refluxing of saturated
solutions, sublimation, and zonal heating. Zonal heating is used primarily for
crystallizing solid solutions or mixtures. Small crystals may sometimes be grown
larger by zonally refluxing a supersaturated solution.
Sublimation may be carried out in a variety of tubes or vessels. Sealed vessels
offer an advantage for sublimation in that the chamber may be evacuated or a partial
pressure of some inert gas may be introduced before sealing the sample in the
apparatus. Sublimation methods consistently produce very high quality crystals.
26
Larger crystals may be grown either by decreasing the thermal gradient or by cyclic
heating and cooling of the sample.
1.6.1.4. Gel diffusion Method
Some compounds, which precipitate as very small crystals immediately upon
synthesis, are extremely insoluble. Suitable crystals of these compounds can often be
prepared by greatly decreasing the rate at which the reactants combine by making the
reactants diffuse through a gel barrier. This is often carried out by forming a gel in a
U-tube and introducing the reactants in the two separate ends of the tube. Such
methods usually take weeks to months to produce good quality crystals depending on
the rate of diffusion of reactant through the gel.
1.6.1.5. Choice of Solvents and Counter ions
There are a number of solvents and counter ions that are commonly found to
be disordered in crystal structures and thus should be avoided if possible. The solvents
giving the most trouble are petroleum ether, mixed hydrocarbons like hexane or
kerosene, and halogenated hydrocarbons such as dichloromethane and chloroform.
Often these solvents occupy sites in a crystal structure that are larger than the solvent
molecule. The halogenated solvents are particularly troublesome because the disorder
includes heavier atoms. Better choices of solvents are benzene, xylene, primary and
secondary alcohols, and tetrahydrofuran. The counter ions most likely to cause
difficulties are Bu4N+, BF4
--, and PF6
--. Some alternative counter ions that are usually
ordered are triflate, BPh4---
, (Ph4P)2N+, and Ph4As
+.
27
1.6.2. Solvent free Methods
There are some methods in which we could use less or no solvents. These
methods, a green route to crystal engineering and polymorph, are used for making
hydrogen bonded adducts or co-crystals154
.
1.6.2.1. Grinding or Ball Milling
In this method, the two solid components are ground together with a ball mill
with or without a small amount of solvent155, 156
. Etter and collaborators investigated
the formation of hydrogen bonded cocrystals by grinding of the solid components,
even in the presence of a third solid component157
. This grinding method was used for
the interconversion of one polymorph to another158
. This method is not popular in
academic research laboratories and is often dismissed as ‘non-chemical’, even though
it is commonly used at industrial level mainly with inorganic solids and materials159
.
1.6.2.2. Kneading and Oligo Diffractrometry
Another process which can be applied in small scale research laboratory is the
so called ‘kneading’160 the use of small amounts of solvent or of a liquid reactant to
accelerate the solid state reactions carried out by grinding or milling. Kneading has
been described as a sort of solvent catalysis of the solid state processes, where the
small amount of solvent provides a lubricant for molecular diffusion. This method is
commonly employed in the preparation of cyclodextrin inclusion compounds. Single
crystals of gases, liquids and their co-crystals can be obtained by an in situ
crystallization technique, called oligo diffractrometry. Nevertheless, this does not
mean that synthesis of co-crystals is routine.
28
1.7. Introduction to the Theory and Experimental Techniques in X-ray
Crystallography
Crystal structure analysis via X-ray diffraction is an analytical technique,
which uses the diffracted X-ray intensities from the crystal. The main theme of single
crystal X-ray structure analysis in crystallography is to locate the exact position of
atoms in the unit cell. Among the various techniques available for molecular structure
determination, X-ray crystallography provides unambiguous information about the
structure of molecules. The central concept in this method is the binding forces that
keep the atoms and molecules together in a crystal. So the ultimate aim of X-ray
crystallography is to understand the nature of this force and thus to predict the
chemical and physical properties of the substance through X-ray diffraction.
Precisely, it gives the information about the geometrical parameters such as bond
length, bond angle, torsion angle and thermal parameters of the atoms in a molecule.
Moreover, the intra- and intermolecular bonding can also be determined.
1.7.1. Single Crystal X-ray Diffraction
To determine the structure using single crystals, one should know the
experimental procedures of single crystal X-ray diffractrometry like data collection,
the theoretical background of the techniques of structure solution and refinement.
Here the pattern produced by the diffraction of X-rays through the closed spaced
lattice of atom in the crystal is recorded and analyzed to reveal the nature of the
lattice.
The spacing in the crystal lattice can be determined using the Bragg’s law.
nλ = 2dsinθ
where, n = 1, 2, 3…
29
d = interplanar spacing
θ = angle of diffraction
λ = wavelength of incident radiation.
1.7.2. Experimental
1.7.2.1 Selection of Single Crystals
To evaluate the quality and appropriate size of crystalline samples, the
samples should be examined under low power magnification (10X to 40X). Good
crystals usually have smooth flat faces and sharp edges. The selected crystal should
show no obvious external twinning (e.g. reentrant faces or different parts of the
crystal extinguishing at different rotation angles under a polarizing microscope). The
crystal chosen for analysis needs to be large enough to produce an adequate
diffraction pattern and, at the same time, as small as possible to minimize absorption
problems. The calculation of structure factor amplitudes assumes that the crystal is
being completely bathed in a uniform beam of X-rays. Since the uniform region of the
X-ray beam is about 0.5 mm in diameter, this is taken as the maximum dimension of
any crystal. For most samples, a minimum dimension of 0.1 mm is needed to produce
adequate X-ray scattering. Compounds with few atoms or very heavy atoms can have
all three dimensions toward the small end of this 0.1 to 0.5 mm range. The best
crystals for compounds with many light atoms should have all three dimensions
toward the large end (0.4-0.5 mm) of this range.
1.7.2.2. Crystal Mounting
Crystal mounting must be rigid to hold the sample in the same orientation and
must minimize the amount of extraneous material that is in the incident and diffracted
30
beam paths. The sample support is usually made from an amorphous material such as
glass that is held in a metal pin and clamped on a goniometer head. Solid glass fibers
may be used; however, fibers pulled from glass tubing are actually small capillary
tubes and are more rigid than solid glass fibers. These narrow tubes also place less
non-crystalline material in the X-ray beam path than solid fibers. Air stable crystals
are usually glued (using epoxy, Elmers/water, Duco/amyl acetate, etc.) to the end of a
glass fiber. The sample should be mounted with its smallest surface on the end of the
glass fiber to minimize absorption effects and to minimize background scattering
from the sample mount. Mildly air unstable compounds can be coated with epoxy or
an inert viscous material such as Paratone N™ or Krytox™ oil. These mountings are
usually carried out in an inert atmosphere such as a dish filled with argon gas. The
crystal is prevented from decomposition during data collection by cooling the sample
in a chilled, inert (nitrogen) gas stream.
1.7.2.3. Unit Cell Parameters
The structural units which are termed unit cells are repeated regularly and
indefinitely in three dimensions in space. The shape of the unit cell is described by six
parameters. These six parameters are three axial lengths, designated as a, b and c and
three inter axial angles α, β and γ. The unit cell has a definite volume V, which
contains the atoms and molecules necessary for generating the crystal. Amorphous
solids lack the long range order present in crystals161
.
Each crystal can be classified as a member of one of seven possible crystal
systems or crystal classes that are defined by the relationship between the six cell
parameters. The structure of the given crystal may be assigned to one of the 230 space
groups. Certain space groups occur more frequently than others. According to the
31
Cambridge Structural Data Base162
, about 76% of all organic and organo metallic
compounds crystallize in only 5 space groups, P21/C, P212121, P-1, P21 and C2/C.
1.7.2.4. Intensity Data Collection
Two general methods are available for intensity data collection.
(i) Photographic method in which the diffracted beam is detected by the
photographic film and then the intensity information is collected from the film.
(ii) Quantum counting device that measures the number of photons directly
(Diffractrometer or Counter).
Three decades ago photographic film method163
was the only possible method
for intensity data collection. Today’s data collection is executed by automated
diffractrometer. Figure 1.16 represents an X-ray diffractrometer.
Figure 1.16 Bruker’s Apex-II CCD Area Detector
32
1.7.2.5. Data Reduction and Structure Solution
The procedure followed to obtain the relative structure factor amplitudes from
the raw integrated intensities is called data reduction.
The structure of the molecule is obtained by a Fourier transform of the
observed amplitude Fhkl. The main theme of single-crystal analysis in
crystallography is to locate the exact position of atoms in the unit cell. If the structure
factors and phases are known, electron density of the unit cell can be calculated
1.7.2.6. Absorption Correction
Some absorption will take place if an X-ray is transmitted through a crystal i.e.
reduction in intensity. The fraction of radiation transmitted
T=I/Io exp (-μt)
where Io is the intensity of the beam, I is the transmitted intensity through the crystal,
t is the thickness of the crystal μ is the linear absorption coefficient (mm─1).
1.7.3. Objectives of the Present Work
1. To develop well-defined supramolecular structures via multiple hydrogen bonds
by self-assembly of components containing complementary array of hydrogen
bonding sites.
2. To use pyridine-2,3-dicarboxylic acid, N-phenyl anthranilic acid, o-formyl
phenoxy acetic acid, p-formyl phenoxy acetic acid , p-formyl phenoxy propionic
acid, eosin, and bases DABCO, 4,4'-bipyridine, stien, and caffeine in view of their
hydrogen bonding ability.
3. To record IR, 1H NMR, TGA/DTA, elemental analysis and single crystal XRD for
the co-crystals obtained.
33
4. To analyze hydrogen bonding interactions, π-π interactions and other non-covalent
interactions involved in the synthesized co-crystals.
5. To study the structural organization in these materials by applying Etter’s graph
set notations to the various types of hydrogen bonding interactions involved.
6. To study the antimicrobial and antifungal activities of the synthesized materials.
7. To study the antioxidant activities of some of the synthesized materials.
34
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