Document Type dissertation Author Name Navare, Pranoti URN etd-053112-134137 Title Resolution of pharmaceuticals via crystallization on chemically modified surfaces Degree PhD Department Chemistry & Biochemistry Advisors John C. MacDonald, Advisor G. Tayhas R. Palmore, Committee Member Robert E. Connors, Committee Member George A. Kaminski, Committee Member Shawn C. Burdette, Committee Member Keywords chiral surfaces enantioselective crystallization Date of Presentation/Defense 2012-05-24 Availability unrestricted
We are investigating resolution of chiral drugs via crystallization on self-assembled monolayers functionalized with achiral and chiral molecules that exhibit varying hydrophobicity/hydrophilicity as a means to bring about enantioseparation. Two goals of this work are to determine (1) whether chiral surfaces can act as templates that bias molecular aggregation at the surface to favor single enantiomers thereby inducing nucleation of conglomerates over racemic crystals, and (2) whether chiral templating can be used to induce selective nucleation of one enantiomer leading to high enantiomeric excess. Racemic compounds being investigated include the antibiotic 3-phenyllactic acid(3PLA) and the muscle-tissue repairing amino acid N-acetylleucine(NAL). Achiral and chiral alkanethiols were self-assembled onto 2D gold substrates by overnight immersion of the gold slides in ethanolic solution of the alkanethiols. The functional groups deposited on the SAM were characterized by grazing incidence IR spectroscopy, contact angle goniometry and ellipsometry. The contact angle and ellipsometry measurements showed that the cysteine SAMs form a bilayer consisting of monolayers of cysteine covalently bonded to gold covered by an overlayer of cysteine. The approach of using chiral templates to induce enantioselective nucleation of racemic drugs on the chiral surface via crystallization was first demonstrated for 3-phenyllactic(3PLA). Homochiral crystals (1), and conglomerates (3) formed from aqueous solution as needles, whereas heterochiral racemic crystals (2) formed from 3:1 hexanes-ethyl acetate as rectangular blocks. A comparison of the thermal stability of the three crystalline forms showed that the crystals of 1 and 3 exhibit greater thermal stability than crystals of 2 such that the racemic form does not appear in the phase diagram. We showed that chiral SAMs of cysteine were able to resolve enantiomers of racemic 3PLA effectively with up to 30% enantiomeric excess in bulk samples of crystals, and that the enantiomer in excess could be controlled based on the choice of D- or L-cysteine as the chiral template. Moreover, crystals of D- or L-3PLA grew oriented with a high degree of selectivity for attachment on the (004) face. We show that the presence of the excess enantiomer (D- or L-3PLA) present in solution acts as an additive to cause a change in the habit of L- or D-3PLA on L- or D-cysteine SAM. We also demonstrated the enantioselective crystallization on chiral SAMs for N-acetylleucine (NAL) which gave a higher enantiomeric enrichment with upto 80% ee. A novel approach of using chiral drugs as templates to amplify the chirality for better self-recognition was designed and SAMs were formed from cysteamine with an overlayer of L-3PLA. As a proof of concept, crystallization of racemic 3PLA on L-3PLA/cysteamine SAMs gave 24% enantiomeric enrichment and our results are comparable to cysteine SAMs. These results confirm our hypothesis that the molecular aggregation on D- and L-cysteine occurs via specific diastereomeric hydrogen-bonding interactions that discriminate between the two enantiomers, thereby promoting enantioselective nucleation and facial selectivity of chiral drugs.
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