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

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 1841 - 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

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

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

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, 640-655, DOI: 10.1039/C5CC08216A 5

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

PHARMACOKINETIC METHODS Case Study: 1:2 cocrystal of LiCl/Leucine PHARMACOKINETIC METHODS • Sprague Dawley Rats Weighing 200-250g (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 12 2017, Molecular Pharmaceutics, 2013 7

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 EP16167817 8

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, 10686. 2) Sholl, D. S. and Lively, R. P. Nature, 2016, 532, 435. 9 9