UCL SCHOOL OF PHARMACY
PHAYG062 Preformulation
Physical form I: Crystalline materials
Today’s learning objectives
• To know the range of solid-state forms available
• To define a crystalline material
• To describe
– Unit cells
– Habits
• To understand how crystallisation conditions affect habit
• To explain the thermodynamic basis for formation of crystalline
materials
Physical form
• Applies to the solid-state only!
• The single biggest factor affecting the performance, developability,
patentability, manufacturability and profit of a drug
• One drug can have many solid state forms
– Crystalline (Polymorphs)
– Habits
– Amorphous
Basic overview of solid forms
Molecular weight
Organic molecular solid
Amorphous Crystalline
Polymorphs Hydrates
Monotropic Enantiotropic Reversible Non-reversible
All can have numerous habits
Crystalline materials
• Crystals contain molecules aligned in a repeating, 3-dimensional
pattern
• In other words, every single molecule in the crystal is in structural
alignment with its near neighbours
• The smallest group of molecules that defines the structural
arrangement is called the unit cell
Ibuprofen
Aspirin
An analogy
Crystalline materials
• The unit cell repeats in three dimensions, forming a crystal lattice
• Bravais worked out there are only 7 basic unit cell geometries
Name Axis rules Angle rules
Triclinic a≠b≠c α≠β≠γ
Monoclinic a≠b≠c α = γ = 90o ≠ β
Orthorhombic a≠b≠c α = β = γ = 90o
Tetragonal a=b≠c α = β = γ = 90o
Hexagonal a=b≠c α = β = 90o γ = 120o
Rhombohedral a=b=c α = β = γ ≠ 90o & <120o
Cubic a=b=c α = β = γ = 90o
Unit cells
• The basic cells assume a single point at each corner
• Also possible to have molecules located
– At the centre of the unit cell (body centred)
– At the centre of each face of the unit cell (face centred)
– At the centre of opposing faces of the unit cell (base centred)
• In total, 42 possible Bravais lattices, but in practice only 14 are
unique (the others can be shown to be mathematically equivalent)
Triclinic
Rhombohedral
Tetragonal
Monoclinic
Cubic
Orthorhombic Hexagonal
• Note that in addition, planes may exist within unit cells (identified with
a numbering system called Miller indices)
Crystal habit
• The unit cell repeats in three dimensions, producing the
macroscopically observed crystal
• Shape of crystal is called its habit
• Only 6 basic habits listed in the USP
Crystal
habit
• The
unit
cell
repeats
in
three
dimensions,
producing
the
macroscopically
observed
crystal
• Shape
of
crystal
is
called
its
habit
• Only
6
basic
habits
listed
in
the
USP
• Crystal
habit
may
significantly
affect
processability
of
the
drug
(affecBng
flow,
passage
through
needles
or
filters
etc)
but
not
chemistry
• SelecBon
of
crystal
habit
almost
as
important
as
selecBng
physical
form
• Habit
can
oGen
be
controlled
through
solvent
selecBon
or
addiBon
of
habit
modifiers
Growth of crystal habits
• Why should crystals grow into different habits?
• Because all molecules are aligned, each face of a crystal will have
different functional groups exposed, and so different properties
• Since crystals grow by deposition of solute molecules, changes in
chemistry (and solvent) might lead to preferential deposition on
certain faces
Note: Fastest growing face will also become smallest face (and in the limit,
will disappear) OR largest face is the slowest growing
• Preferential growth on a plane can significantly alter macroscopic
shape of crystal
Crystal formation
Energy or volume
Solid Liquid
Phase transformation
Temperature
mp
Polymorphism
• Means
‘many
forms’
• In
other
words,
one
drug
substance
possessing
more
than
one
unit
cell
Form I Form II
Polymorphism
Lower density Higher density
Lower lattice energy Higher lattice energy
Lower melting point Higher melting point
Higher (ideal) solubility Lower (ideal) solubility
Faster dissolution rate Slower dissolution rate
Possible fracture line
Form I Form II
What would happen if perfect crystal did not
form?
Energy or volume
Solid Liquid
Phase transformation
Temperature
mp
What would happen if perfect crystal did not
form?
Energy or volume
Solid Liquid
Supercooled liquid
Form II (metastable)
Form I (stable)
Temperature
mpII mpI
Solubility of polymorphic forms
• Since heat of fusion and melting point of each form is different,
ideal solubility will be different
−Δ fus H Δ fus H
ln x2 = +
RT RTm
• Higher when either ΔfusH or m.p. lower
• This has a consequence if all sample dissolves
Solution filtered to remove
excess solid
So,ms Solubility of metastable
form
Concentration (mg mL )
-1
So,s
Time (min)
Polymorphs
• Polymorphs are thermodynamically distinct
• The form with the lowest energy is the stable form
• All others are metastable with respect to the stable form
Over time all metastable forms will ultimately
convert to the stable form
• Is the stable form always the stable form (i.e. with respect to
temperature and pressure)
• No. Sometimes the form that is most stable can change
Effect of polymorph on drug product performance
Serum levels obtained with suspension of chloramphenicol palmitate
( ) 100 % form B ; ( ) 50 % form A / 50 % form B: ( ) 100 % form A
24
22
20
Serum levels (µg ml-1)
18
16 *Aguiar et al, J. Pharm. Sci., 56 (1967) 847
14
12
10
8
6
4
2
1 3 5 7 9 11 24
Time (hours)
Summary
• Crystalline materials are highly ordered and can be defined by a
unit cell
• Forms of the same molecule with different unit cells are
polymorphs
• Growth of a crystal will depend on conditions – macroscopic
shape of crystal is the habit
• If other components are in the unit cell, the material is a pseudo-
polymorph
