University Master’s Degree in Pharmaceutical Chemistry

Identification and Structural Characterization

Crystallography
and X-ray
Diffraction
applied to the
Pharmaceutical
Industry

MASTER’S DEGREE IN PHARMACEUTICAL CHEMISTRY

 Index
▪ Crystallography, basic notions
▪ Introduction
▪ Single crystals characteristics
▪ Single crystals growth methods
▪ Geometric crystallography
▪ Crystallography laws
▪ Symmetry
▪ Single crystal X-ray Diffraction
▪ Characteristics
▪ Equipments
▪ Powder X-ray Diffraction
▪ Characteristics (quantitative)
▪ Equipments
▪ Simulation from PXRD
geometric crystallography
❖ Crystallography laws
❖ symmetry
❖ symmetry operations
❖ symmetry elements
❖ point groups
❖ Bravais lattices and crystal systems
❖ space groups
 Aspirin

Crystallographic Data
Empirical formula C9 H8 O4
Formula weight 180.16
Radiation CuKa
Wavelength 1.54178 Å
Crystal system monoclinic
Space group P21/c
Unit cell dimensions
a = 11.430(1) Å
b = 6.591(1) Å
c = 11.395(2) Å
b = 95.68(1) º
Volume 854.2(4) Å3
Z 4
Density (g/cm3) 1.401
Crystal size (mm) 0.1 x 0.2 x 0.2
R1 (%) 4.6
Rw (%) 7
1 crystallography
laws
 1. CRYSTALLOGRAPHY LAWS

The three fundamental laws of crystallography have been formulated

on the basis of the study of the external shape of crystals:

1. Law of constancy of dihedral angles

2. Law of rational indices

3. Law of constancy of symmetry

 1. CRYSTALLOGRAPHY LAWS

A little bit of history

• Johannes Kepler (1611): symmetry in ice crystals

• Niels Stensen (1638-1686):

1. Fundamental law on the CONSTANCY of INTERFACIAL ANGLES.

Crystals of the same substance can have very different aspects, depending
on the number and size of the faces, but the angles between the
corresponding faces remain constant at the same conditions of P and T

Drawings of quartz crystal sections

• Jean-Baptiste Louis Romé de l’Isle

(1783): confirmation and demonstration of
the above law for crystals of many other
substances. Work Crystallographie,
beginning of modern crystallography
 1. CRYSTALLOGRAPHY LAWS

• René Just Haüy (1784): “Essai d’un Théorie sur la structure des
Cristaux” based on his views on the laws of Symmetry, Rational Indices
and the Constancy of the Crystalline Form

2. Law of RATIONAL INDICES. The three-sided intersection edges of a

crystal make it posible to define a system of coordinate axes. The
distance at which a fourth fase cuts each axis is considered the unit of
measure on this axis. All other faces of the crystal cut these axes at
distances whose ratio to the lenghts defined as units are rational numbers
and generally simple.
 1. CRYSTALLOGRAPHY LAWS

3. Law of CONSTANCY of SYMMETRY. All crystals of the same

substance have the same symmetry, regardless of the faces they present

Cubic, octahedral and dodecahedral pyrite crystals

 1. CRYSTALLOGRAPHY LAWS

Once the LAWS of CRYSTALLOGRAPHY are enunciated, if the crystals

are really formed by the repetition of some PARALLELEPIPED CELLS
which contain atoms, molecules or ions…

cell PARAMETERS: a, b, c, a, b, g define the UNIT CELL

the complete crystal is obtained by means of TRANSLATIONS of the main cell

 1. CRYSTALLOGRAPHY LAWS

The choice of the cell is NOT unique, there are infinite possibilities

PRIMITIVE CELL: unit cell that has the smallest possible volume
 1. CRYSTALLOGRAPHY LAWS

Once the LAWS of CRYSTALLOGRAPHY are enunciated, if the crystals

are really formed by the repetition of some PARALLELEPIPED CELLS
which contain atoms, molecules or ions…

How many SYMMETRIES do crystals present in NATURE?

How many different three-dimensional NETWORKS will fill the

space completely with these cells?
 1. CRYSTALLOGRAPHY LAWS

• Johann Friedrich Christian Hessel (1830): demonstrated that, as a

consequence of the Haüy Law of Rational Indices, different
morphologies can be combined to give 32 types of crystalline
symmetry (point groups)

• Auguste Bravais (1848): discovered that there are only 14 unique

lattices in three-dimensional crystalline systems

• Evgraf S. Fedorov y Arthur Schoenflies (1890-1891): deduced the

230 possible space groups restricting the repetitive distribution of the
crystal construction units
2 symmetry
 2. SYMMETRY

Monet Escher

Unique elements Repetitive elements

The PERIODIC media are REPETITIVE, present SYMMETRY

 2. SYMMETRY

SYMMETRY: coincidence of structural or morphological motifs through

mathematical operations called symmetry operations, these operations
are grouped into symmetry elements.

An important part of Cystallography is symmetry, both at the atomic

ordering (spatial symmetry), and at the macroscopic level in the
morphology of crystals (point symmetry).

To fill a plan with tiles (TESSELLATE THE PLANE) periodically, there

are four strategies:

• translation
• rotation
• reflection
• displacement symmetry
 2. SYMMETRY

17 flat groups

Alhambra
 2. SYMMETRY

Symmetry in crystals

The description of the symmetry is done through several

conceptual notions that from less to more hierarchical degree:

• symmetry operations

• elements of punctual symmetry

• point groups

• crystal systems

• space groups
 2. SYMMETRY

Symmetry operations

A point symmetry operation relates two identical geometric elements

(faces, edges or vertices) of a polyhedron by means of a mathematical
operation.

• rotations around an axis

• reflections
• inversions
• rotations combined with an inversion

A spatial symmetry operation relates identical positions by means of a

mathematical operation.
• translations
• helicoidal axes
• glide planes
 2. SYMMETRY

Symmetry operations

Rotation

Reflection Inversion
Translation
 2. SYMMETRY

Symmetry operations
The crystalline medium is periodic and as a result of this periodicity, the
rotations of spatial symmetry operations cannot be of any value.
PERMITTED ROTATIONS both in the internal order of the crystals and
in their external form, are restricted to angles of 60, 90 or multiples of
them.
 2. SYMMETRY

Elements of punctual symmetry

Symmetry elements are sets of symmetry operations that can be
reduced to a single symmetry operation iteratively applied a finite
number of times until the starting geometric element returns to its initial
position. This finite number of times is called the ORDER of the
symmetry element.

• ROTATION AXES
 2. SYMMETRY

BINARY AXIS TERNARY AXIS

The mofif is repeated every 180º The motif is repeated every 120º

QUATERNARY AXIS SENARY AXIS

The motif is repeated every 90º The motif is repeated every 60º
 2. SYMMETRY

• ROTATION – INVERSION AXIS

INVERSION CENTER: primary rotation – inversion axis

A

D
B
0
C C’

B’ D’

A’
_
1

REFLECTION PLANE: binary rotation – inversion axis

_
m 2 m
 2. SYMMETRY

Point groups

Point symmetry groups are sets of symmetry elements. Not all

combinations of symmetry elements are posible and therefore there is a
finite number of point groups: 32

Inversion Rotation
axis
i
1, 2, 3, 4, 6

Reflection
Roto-Inversion
planes
m 1, 2, 3, 4, 6
POINT
GROUPS
 2. SYMMETRY

Point groups

Rules that condition the presence of several elements of symmetry in

the same point group:

• If there is an even rotation axis and a plane of reflection

perpendicular to it, there is a center of symmetry at its intersection

• If a series of symmetry planes are cut into a symmetry axis, there

are as many planes as the order of the axis

• If a rotation axis of order n has binary axes perpendicular to it,

there will be as many binary axes as the order of the axis

• If there is a binary axis perpendicular to a rotation – inversion axis,

whose n order is even, there are n/2 planes intersecting with the
axis and n/2 binary axes perpendicular to it
 2. SYMMETRY

Point groups

• 11 enantiomorphics: 1, 2, 222, 4, 422, 3, 32, 6, 622, 23, 432

_ _ _
• 11 centrosymmetrics: 1, 2/m, mmm, 4/m, 4/mmm, 3, 3m, 6/m, 6/mmm, m3, m3m
_ _ _ _ _
• 10 planes but no centers: m, mm2, 4, 4mm, 42m, 3m, 6, 6mm, 6m2, 43m

Schoenflies notation (old) and Hermann Mauguin notation (international)

 2. SYMMETRY

HERMANN-MAUGUIN notation

• symbols representing the various elements of symmetry

• succession of numbers (rotation axes) and the letter m (plane of reflection)

• X/m represents a reflection plane m perpendicular to a rotation axis of order X

• Xm represents a reflection plane m which contains a rotation axis of order X

• X2 represents a 2-fold rotation axis perpendicular to a rotation axis of order X

• If there is a 3 in the first place of the symbolic notation of a point group, this
group belongs to the trigonal system

• If there is a 3 in the second place of the symbolic notation of a point group, this
group belongs to the cubic system
 2. SYMMETRY

HERMANN-MAUGUIN notation

• three directions of symmetry are distinguished but not all groups have them:

• Triclinic lattices: no direction of symmetry

• Monoclinic lattices: one direction of symmetry
• Trigonal lattices: two directions of symmetry
• Orthorhombic, tetragonal, hexagonal and cubic lattices: three directions

• quaternary rotation axis parallel to z

4/mmm • plane perpendicular to a quaternary rotation axis
• two planes perpendicular to the x, y axes

• two planes perpendicular to the x, y axes

mm2
• binary rotation axis parallel to z
 2. SYMMETRY

HERMANN-MAUGUIN notation

• senary rotation axis parallel to z

6/mmm • plane perpendicular to a senary rotation axis
• two planes perpendicular to the x, y axes

• binary rotation axis parallel to y

2/m • plane perpendicular to a binary rotation axis
• inversion center

6mm • senary rotation axis parallel to z

• two planes perpendicular to the x, y axes
 2. SYMMETRY

MULTIPLICITY of a point group

The multiplicity of a point group is the number of equivalent points by symmetry.

There are point groups of low symmetry, with a single symmetry element and
point groups of high symmetry with several point symmetry elements that globally
can add up to a máximum
SI STEMA of
CRI48 symmetry
STALI operations
NO TRI CLÍ NI CO
GRUPO SIFORMAS
STEMA CRI STALI NO TRI CLÍ NI CO PROYECCI ÓN
FORMAS
CLASE
GRUPO
PUNTUAL FORMAS
ESPECI FORMAS
ALES GENERALES PROYECCI ÓNCA
ESTEREOGRÁFI
CLASE
PUNTUAL ESPECIALES GENERALES ESTEREOGRÁFI CA

Pedial Pediones
Pedial
(Hemiedría) 1 1 Nº operations:
No hay 1 Pediones
hkl
1 No hay
(Hemiedría) hkl

ll
uuaa
Pinacoidal Pinacoide
1 No hay
Pinacoidal
(Holoedría) _ Pinacoide
hkl h kl
(Holoedría) 1 1 Nº operations:
No hay 2hklaascsc h kl
Tabla 4.16
Tabla 4.16
sPP
SI STEMA CRI STALI NO MONOCLÍ NI CO
GRUPO SI STEMA CRI STALI NO
FORMAS MONOCLÍ NI CO
FORMAS PROYECCI ÓN
CLASE
GRUPO
PUNTUAL FORMAS
ESPECI ALES FORMAS
GENERALES PROYECCI ÓNCA
ESTEREOGRÁFI
 (Holoedría)
Pinacoidal hkl h kl
1 No hay
(Holoedría) hkl 4.16
Tabla h kl 2. SYMMETRY
Tabla 4.16
SI STEMA CRI STALI 4.16MONOCLÍ NI CO
TablaNO
MULTIPLICITY of a point group
GRUPO FORMAS
SI STEMA MONOCLÍ NI CO
FORMAS
CRI STALI NO PROYECCI ÓN
CLASE
PUNTUAL
GRUPO SIESPECI
STEMA
FORMASALES GENERALES
CRI STALI NO
FORMAS PROYECCI ÓNCA
MONOCLÍ NI CO ESTEREOGRÁFI
CLASE
GRUPO
PUNTUAL FORMAS
ESPECIALES FORMAS
GENERALES PROYECCI ÓNCA
ESTEREOGRÁFI
CLASE
Esfenoidal Pedión 010 o
PUNTUAL ESPECI ALES GENERALES
Esfenoide ESTEREOGRÁFI CA
(Hemiedría
Esfenoidal 2 2 Nº operations:0 o2
Pedión0 1010
hkl , h kl
Esfenoide
enantiomórfica) Pedión 010 o
Esfenoidal
(Hemiedría 2 0 1 0 h0l
Pinacoides
Esfenoide
hkl , h kl
(Hemiedría
enantiomórfica) 2 0 1 0 h0l
Pinacoides hkl , h kl
enantiomórfica) Pinacoides h0l l
Pediones h0
Domática
Domo
(Hemiedría
Domática m 010
Pediones h0
Pinacoides l
m m Nº operations: hkl , hkl
Domo
hemimórfica)
Domática
(Hemiedría Pediones h0
Pinacoides l 2
010
hklDomo
, hkl
(Hemiedría
hemimórfica) m Pinacoides 010
hkl , hkl
hemimórfica)
Prismática Pinacoides Prisma
2
(Holoedría) m 010 , h0l
Pinacoides hkl hPrisma
kl h kl hkl
Prismática
2
Prismática
(Holoedría) 2/m2 mNº Pinacoides
operations:
010 , h0l 4 hkl hPrisma
kl h kl hkl
(Holoedría) m 010 , h0l hkl 4.17
Tabla h kl h kl hkl

Tabla 4.17
Tabla 4.17

16

16
 2. SYMMETRY
ASYMMETRIC UNIT

Minimum part that by application of symmetry generates the unit cell

Crystal

Asymmetric unit : Z’ Unit cell

Z : number of molecules in the unit cell

 2. SYMMETRY

UNIT CELL TYPES

P primitive F centered on all faces

I body centered C centered on two faces

 2. SYMMETRY

BRAVAIS LATTICES

• In two-dimensional space there are only five possible ways to fill the space
with identical parallelograms and without leaving gaps. They are the oblique,
rectangular, rhombic, square and hexagonal lattices.

• In the three-dimensional space there are fourteen crystal lattices that fill the
space and that can be derived by stacking flat lattices in such a way that
certain elements of symmetry are preserved.
 2. SYMMETRY

BRAVAIS LATTICES AND CRYSTAL SYSTEMS

 2. SYMMETRY

CRYSTAL SYSTEMS

If point groups are grouped by common symmetry, one can find a series of
groups that all have a single binary axis, or a single ternary axis, or a single
quaternary axis… If one starts from the minimum symmetry, for example a single
quaternary axis, one can propose a deductive scheme that allows one to reach
the rest of groups with identical symmetrical characteristics.

Single axis quaternary groups: tetragonal crystal system

• If an inversion center is added to group 4, the group 4/m is generated

• If a binary axis is added to group 4, the group 422 is generated
• If a plane containing the axis is added to group 4, the group 4mm is generated
• If an inversion
_ center is added to group 422, the group 4/mmm is generated
• Group 4 (quaternary inversion axis) _ _
• If a perpendicular binary axis is added to group 4, the group 42m is generated
 2. SYMMETRY
La simetría espacial se elabora también a través de elementos de simetría que incluyen las mismas
operaciones que en simetría puntual añadiendo además la traslación como posible operación.
CRYSTAL SYSTEMS
5.-Grupos de simetría puntual

Los grupos de simetría puntual son conjuntos de elementos de simetría. Estos conjuntos los
presentan los cristales idealizados de los diferentes sólidos cristalinos y se visualizan muy
symmetry de elementos de simetría son posibles y
convenientemente en ellos. No todas las combinaciones
- +
por eso hay un número finito de grupos puntuales, 32:

sistema sistema sistema sistema sistema sistema sistema

Triclinic Monoclinic Orthorhombic Tetragonal Trigonal Hexagonal Cubic
triclínico monoclínico rómbico tetragonal trigonal hexagonal cúbico
1 2 4 3 6 23
1 m 4 3 6
2/m 4/m 6/m m3
222 422 32 622 432
mm2 4mm 3m 6mm
4 2m 3m 6 m2 4 3m
mmm 4/mmm 6/mmm m3m

La notación de los grupos de simetría puntual tiene sus propias normas para cada sistema
Holoedry:
cristalino group
y siempre of greatest
consiste symmetry
en combinaciones within each
de números crystal
que hacen systema ejes de
referencia
rotación o de rotación-inversión y la letra m que denota la presencia de planos de reflexión. Para
algunos grupos aparece una barra oblicua (/) que siempre indica una relación de
perpendicularidad entre un eje de simetría y un plano de reflexión.
2. SYMMETRY
 2. SYMMETRY

SPACE GROUPS

Groups whose elements include the elements of punctual symmetry and

translations. The deduction of all posible ways in which identical objects
(atoms, ions or molecules) can be arranged periodically in the three-
dimensional space is based on the idea of systematically combining the
32 point groups with the 14 Bravais lattices so that each point of the
object has the same point environment but without necessarily being
equally oriented with respect to the nodes of the network.

• translation
• helicoidal axis (21)
• glide plane (a, n, d)

Any chemical compound, however complex it may be, if it crystallises, will

do so in such a way that the symmetry of the arrangement of its atoms can
be ascribed to one of the 230 space groups.
 2. SYMMETRY

Helicoidal axes: rotation followed by translation parallel to the axis

 2. SYMMETRY

Helicoidal axes: rotation followed by translation parallel to the axis

Axis 21
 2. SYMMETRY

Glide planes: reflection followed by translation parallel to the axis

(a, b, c, n, d)
 2. SYMMETRY

Glide planes: reflection followed by translation parallel to the axis

a reflection + translation a/2 b reflection + translation b/2 c reflection + translation c/2
n reflection + translation a/2+b/2, or b/2+c/2, or a/2+c/2
d reflection + translation a/4+b/4, or b/4+c/4, or a/4+c/4

Plane c
 2. SYMMETRY

SPACE GROUPS

The symbols for space groups consist of a capital italic letter indicating the
cell type followed by the Hermann-Mauguin notation of the point group,
including also helicoidal axes and glide planes

Tetragonal point group 4/m

• P4/m
• P42/m
Space groups • P4/n
• P42/n
• I4/m
• I41/a
 2. SYMMETRY

SPACE GROUPS

The symbols of the space groups give us information about the crystal
system and the point group. This is obtained by transforming the
translational elements by the equivalents without translation

Space groups Point groups Crystal system

C2/c 2/m monoclinic

P42/nbc 4/mmm tetragonal

Cmc21 mm2 orthorhombic

 2. SYMMETRY

230 SPACE GROUPS

 2. SYMMETRY

International Tables for X-ray Crystallography

Summary of existing information for Space Group Nº 35

Space group Point group Crystal system

 Aspirin
Crystallographic Data
Empirical formula C9 H8 O4
Formula weight 180.16
Radiation CuKa
Wavelength 1.54178 Å
Crystal system monoclinic
Space group P21/c
Unit cell dimensions
a = 11.430(1) Å
b = 6.591(1) Å
c = 11.395(2) Å
b = 95.68(1) º
Volume 854.2(4) Å3
Z 4
Density (g/cm3) 1.401
Crystal size (mm) 0.1 x 0.2 x 0.2
R1 (%) 4.6
Rw (%) 7
 Final considerations

• The mathematical derivation of the 230 space groups culminates a

research effort spanning more than two centuries.
• A robust and consistent theoretical building was provided for the science
of crystals.
• Despite its consistency, there was no solid basis.
• The ideas about how the structures of the crystals should be were based
on the observation of the external morphology of the real crystals.
• The nineteenth century ended without any proof that the crystals were
made up of atoms ordered periodically according to a series of specific
patterns.
• It was not until 1912 that it was irrefutably demonstrated that the atoms
inside the crystals were arranged according to three-dimensional
networks thanks to the discovery of X-rays.