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