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.

3

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

5

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

6

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.

7

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.

8

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

9

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”.

11

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

.

12

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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