Why Crystals Matter to the Real
World
Outline of lecture
• What is a crystal?
• Crystals are everywhere in Nature
• Applications of crystals: drug products
• Applications of crystals: porous materials
First some ancient history – 2000+ years ago
D- and L- quartz: chiral crystals
The original “crystal”, named after the Greek
word κρύσταλλος (krystallos) meaning clear ice
(thought at time to be a hard version of ice)
Pasteur’s spontaneous resolution
experiment in 1848 started the
field of stereochemistry
The basics: molecules form crystals
solution
supersaturated solution
crystal
When solutions are brought to a state of supersaturation in a controlled
fashion, normally by cooling or evaporation, the vast majority of substances
form one or more crystalline solids.
Crystal = a regular repeating array of molecules or ions that extends in 3D.
The basics: amorphous solids also exist
Amorphous solid: No long-range repeating pattern of molecules or ions.
Typically prepared by fast cooling, anti-solvent and other methods that do
not give crystals time to form. Always less stable than crystalline solids
Outline of lecture
• What is a crystal?
• Crystals are everywhere in Nature
• Applications of crystals: drug products
• Applications of crystals: porous materials
Peacock butterfly
thanks to Kieran Hodnett of SSPC
Peacock butterfly magnified
thanks to Kieran Hodnett of SSPC
Further magnified wing
thanks to Kieran Hodnett of SSPC
Butterfly wing magnified 50x
thanks to Kieran Hodnett of SSPC
Butterfly wing scales magnified 200x
thanks to Kieran Hodnett of SSPC
Butterfly wing scales magnified 1000x.
thanks to Kieran Hodnett of SSPC
Butterfly wing scales magnified 5000x.
thanks to Kieran Hodnett of SSPC
Material = nanocrystals of chitin = the same
substance that forms exoskeletons of shellfish
and beetles
thanks to Kieran Hodnett of SSPC
Magnified Kidney
Stone
thanks to Kieran Hodnett of SSPC
Material = nanocrystals of calcium phosphate =
the same substance that forms bones and teeth
thanks to Kieran Hodnett of SSPC
Crystals of
cocoa butter
in chocolate
Active
ingredient =
theobromine
thanks to Kieran Hodnett of SSPC
Dental plaque
= crystals of
calcium
phosphate +
biomolecules
thanks to Kieran Hodnett of SSPC
thanks to Kieran Hodnett of SSPC
Pharmaceutical Science
Crystal forms are preferred for oral delivery of APIs
•
•
•
•
•
•
•
Purity
“Processability”
Patentability
Physicochemical properties
Stability
Reproducibility
Cost of delivery
i.e. material properties
make the medicine
BUT: 85% of New
Chemical Entities (NCEs)
exhibit “low solubility”
”
Outline of lecture
• What is a crystal?
• Crystals are everywhere in Nature
• Applications of crystals: pharmaceuticals
• Applications of crystals: porous materials
Application 1
Early Drug Discovery and Development
Pre-formulation
Formulation
Molecules
Materials
Medicines
Medicinal Chemistry
Drug Substance(s)
Drug Product
le
API
Active Pharmaceutical
Ingredient
21
Excipients
What is a Cocrystal?
“…solids that are crystalline single phase materials composed of two or
more different molecular and/or ionic compounds generally in a
stoichiometric ratio…”1
Ionic Cocrystals
Molecular Cocrystals
• Two or more different
neutral coformers
• Typically held together
by halogen or H-bonds
22
• Three or more components with
at least one salt plus a nonvolatile neutral molecule (or an
additional salt)
• Typically sustained by chargeassisted H-bonds or coordination
bonds
1. Atimupala, S., Cryst. Growth Des., 2012, 12, 2047
Why Ionic Cocrystals
Ionic cocrystal = 3 variables = diversity
• Can use same components as molecular cocrystals, i.e. GRAS
• Introduces salt option as part of complex, i.e. lithium chloride + L-proline
LiX.aM.bS
Employs stronger (robust) interactions, more reliable
square grid
23
diamondoid
Ong, T. et al., J.Am.Chem.Soc., 2011, 133, 9224
abw zeolite
Ionic Cocrystals Chronology
1783 - Rome de l’Isle crystallizes NaCl
with octahedron morphology
(instead of cubic) in presence of
urine1
1843 – Discovery of a compound
formed by sodium chloride and
glucose2
1963 – Publication of sodium chloride,
urea and water (1:1:1)
1991 – Structure report of sodium
chloride, glucose and water
(2:1:1)
NaCl
24
1. Rome de L‘Isle, Crystallographie, 2nd ed. Paris, 1783, 1, 379
2. Kobell, F, V. J. für Prakt. Chemie., 1843, 28, 489-491
NaCl·Urea·H2O
Other motivation to study crystal forms of drug substances
The $30 billion patent: ranitidine HCl (Zantac®) form II
FORM 1
Crystal forms of drug
substances are preferred
for oral delivery = highly
valuable materials for
drug products
Form 2 is:
• Novel
• Not obvious
• Has utility
FORM 2
Chem. Commun, 2016, 52, 640-655, DOI: 10.1039/C5CC08216A
Outline of lecture
• What is a crystal?
• Crystals are everywhere in Nature
• Applications of crystals: pharmaceuticals
• Applications of crystals: porous materials
The Porous Materials Universe
Hybrid Ultramicroporous Materials
28
Metal-Organic Materials – MOMs
Also known as MOFs, PCPs, PCNs,…
[Zn(4,4’-bipy)2(H2O)2•SiF6]n
Gable, R. W.; Hoskins, B. F.; Robson, R. A.
JCS Chem. Commun. 1990,1677.
METAL or Molecular Building Block,
MBB, makes three or more
connections: is a node
ORGANIC molecule makes only two
connections: is a linker
Many combinations = many
structures (est. 20,000)
R.A. Robson
Nanoscale cavity
= a MATERIAL
The first extra-large surface area materials
ca. 1900m2/g
ca. 3000 m2/g
[Cu3(BTC)2(H2O)3]n, HKUST-1 (tbo)
[(Zn4O)(bdc)3]n, MOF-5 (pcu)
Chui, S.S.Y.; Lo, S.M.F.; Charmant, J.P.H.;
Orpen, A.G.; Williams, I.D., Science, 1999, 283,
1148-1150.
Li, H.; Eddaoudi, M.; O'Keeffe, M.; Yaghi, O.
M., Nature, 1999, 402, 276-279.
Why is empty space useful?
Things can go in (trapped) and out (controlled release)
Zeolites such as zeolite A, zeolite XY
(alongside) and rho-zeolite are made
industrially (millions of tons/year).
They are widely used in gas
purification, water softening, drug
delivery and petroleum refining.
MOMs exhibit up to 7000m2/g surface area
Existing materials are generally limited to 1000 m2/g
13600m2
9000m2