1. Cocrystals can be designed
Pharmaceutical cocrystals 101: carboxylic acids
Aspirin, Ibuprofen
Carbamazepine, Tegretol®
Prozac®
Itraconazole 1

2. Cocrystals 201: Ionic cocrystals rule
Molecular cocrystals vs. ionic cocrystals
“…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
date to 1783 – NaCl urea
Molecular Cocrystals
date to quinhydrone
Three or more coformers with at least one salt plus a non-volatile neutral molecule (or an additional salt)
Typically sustained by charge-assisted H-bonds or coordination bonds
Two or more different neutral coformers
Typically held together by halogen or H- bonds
1. Atimupala, S., et al. Cryst. Growth Des., 2012, 12, 2047 2 2

3. FDA approved pharmaceutical cocrystals
Cocrystals 301: regulatory risks are low
Beta-ChlorTM
Molecular cocrystal
(charge assisted)
Increased thermal stability,
less GI reactions
1983
Ionic Cocrystal
Optimised physical properties, retains efficacy
1963
Molecular cocrystal
Ertugliflozin-L-pyroglutamic acid
1999
2017
Molecular cocrystal (charge assisted)
Improved aqueous solubility
2015
Ionic Cocrystal
Combined drugs for dual-action properties with significant mortality benefit
2015
2002
Ionic Cocrystal
Improved stability
Ionic Cocrystal
Improved processing properties
+ Ipraglifoxin L-proline, Suglat®
+ Theophyliine sodium glycinate 3

4. Coformer Libraries Cocrystals 401: there are so many “safe” coformers
Vitamins
Polyphenols/
Phenolic acids
Flavonoids
Salts
Purines
Nicotinamide
LD50: 5 g/kg
Water Solubility: High
Gallic acid
LD50: 5
Water Solubility: Medium
EGCg
LD50: 2.17
Inorganic Salts
NaCl
NH4Cl
Mgsulfate
Adenine
LD50: 0.8
Water Solubility: Low
L-ascorbic acid
LD50: 11.9
curcumin
LD50: 2
Water Solubility: Low
quercetin
LD50: 0.16
Organic base hydrochloride salts
Metal salts of organic anions, especially carboxylates and sulfonates
Alkylammonium salts of inorganic anions
Theobromine
LD50: 1.0
Water Solubility: Medium 4

5. Chem. Commun, 2016, 52, 640-655, DOI: 10.1039/C5CC08216A
The Cocrystal Advantage
Better properties = better medicines
Cocrystals - a low risk, low cost, high reward route to new and better medicines
Control over physicochemical properties
New ip opportunities
No change in molecular structure
FDA has endorsed cocrystal drug substances but regulatory requirements still to be unified
505(b)(2) pathway possible for new drug products
Issues with manufacture
Higher mass of dosage form
Chem. Commun, 2016, 52, , DOI: /C5CC08216A 5

6. Case study: lithium as a target for ionic cocrystals
Can we teach an old dog new tricks?
Li metal discovered in 1800
Used as a medication since the 1860’s
“Active ingredient” of 7-Up until 1930’s (AW of Li = 7)
In 1947 Australian psychiatrist John Cade noticed Li is effective against mania
Li is now an anti depressant drug used for bipolar disorder and psychotic behavior - several Li salts are currently marketed
But there are problems with lithium:
The transport of Li to brain is low compared to other organs and tissues.
After 24 hours the Li concentration is at its maximum so multiple doses are required in treatment.
There is a narrow therapeutic index (safety margin)
Specific aim: Change composition (speciation) of API to improve brain bioavailability and metabolism of lithium
Possible indications: Fragile X syndrome; teen suicidality, Alzheimer’s 6

7. PHARMACOKINETIC METHODS
Case Study: 1:2 cocrystal of LiCl/Leucine
PHARMACOKINETIC METHODS
• Sprague Dawley Rats Weighing g (n=12 per formulation group; N=24)
• Dosed via Oral Gavage with 4meq Lithium as LiCl and LiClLeu
• Euthanized at 2 (n=4), 24 (n=4), and 48 (n=4) hours
• Blood was collected by cardiac puncture (3 cc)
• Perfused with a pressure-controlled pump to maintain microvasculature integrity
• Blood and brains collected and analyzed for Li content (AAS)
Doug Shytle
US Patent 9,840,521 issued December , Molecular Pharmaceutics, 2013 7

8. New lithium compositions
Stability and bioavailability improved by amino acids
Coordination Polymer
(Inorganic anion/Organic anion/amino acid)
Anhydrous CPs
= Better stability + bioavailability
Salt
Molecular Complex
Complex Anion
(Lithium part of anionic complex)
US Patent 9,840,521
European patent application EP 8

9. Application 2: Gas/Vapour Purification/Storage
Chemical industry = $5.6 trillion = ca. 7% of world GDP
Age of Gas – The use of gases as energy resources and commodities1
40% of energy used in chemical industry is for separations/purification = 15% of the World’s energy use2 could triple by 2050
On-board vehicular transport – CH4 ; H2
Greenhouse Gas Remediation – removal of CO2 (CCS or CCU)
Water purification
1) Kitagawa, S. Angew. Chem. Int. Ed., 2015, 54,
2) Sholl, D. S. and Lively, R. P. Nature, 2016, 532, 435. 9 9