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Thesis-1982D-K435m.Pdf METAL ION - DRUG INTERACTIONS IN SOLUTIONS By NITAYA KETKEAW "' Bachelor of Science Chiengmai University Chiengmai, Thailand 1975 Submitted to the Faculty of the Graduate College of the Oklahoma State University in partial fulfillments of the requirements for the Degree of DOCTOR OF PHILOSOPHY December, 1982 l~1<:.~is \q 1i ~D K l.~:lj M ~·IV' ----- METAL IN SOLUTIONS Thesis Approved: Dean of the Graduate College ii 1155645 ,. ACKNOWLEDGMENTS I wish first to express my gratitude to Dr. Neil Purdie for his patience, understanding and invaluable guidance through out this study, and for his assistance in the preparation of this manuscript. Appreciation is expressed to Dr. Larry E. Halliburton for the use of ESR facilities and his assistance in obtaining the ESR spectra, and to Dr. Tom E. Moore, Dr. Elizabeth M. Holt, Dr. J. Paul Devlin and Dr. Liao Ta-Hsiu for serving on the committee. Special thanks are extended to my fellow graduate students and to the faculty and staff of the Chemistry Department for their encouragement. I would also like to express gratitude to my parents and my husband for their patience and unfailing encouragement throughout the long years. iii TABLE OF CONTENTS Chapter Page I. INTRODUCTION • 1 Statement of the Problem 8 II. BACKGROUND AND THEORY 10 Circular Dichroism . • • 10 Origin of Light Polarization . • • • 10 Electron Spin Resonance . • • • 19 Hyperfine Structure .• . .. • 24 g - Factor • • • . • . • . • • • 30 Interpretation of ESR Spectra 31 III. EXPERIMENTAL . 33 Instrumental . • . • • • . • 33 Chemicals . • • . • • • • . • . 35 Experimental Procudures . • • • • • 36 CD and UV-Visible Measurements • 36 Acid and Base Titrations of Morphine in Aqueous Solution . • • • . • 36 Metal Ion - Drug Interactions in Aqueous Solution • • • 36 Reactions of Drugs with Con- centrated Sulfuric Acid • 37 Pseudomorphine Solutions 37 ESR Measurements • . • • 37 NMR Measurements . • • • . • . 39 IV. EXPERIMENTAL RESULTS .•.• 40 Isotropic CD Spectra . • . 40 Acid and Base-Titrations of Morphine Free Base in Aqueous Solution • • • • • • • • • 40 Metal Ion - Drug Interactions in in Aq~ious Solution . • . 48 ca3+ - Morphine Interaction 48 Fe+ - Drug Interactions • • 50 Ag - Morphine Interaction . 51 Pseudomorphine Solutions • • • • 54 iv Chapter Page Reactions of Drugs in Concentrated Sulfuric Acid •..••.•...• 59 Reactions of Drugs with Color Test Reagents in Concentrated Sulfuric Acid . 64 UV-Visible Studies • . • . • 65 CD Studies • • . • . • • . • 65 ESR Measurements . • . 81 NMR Measurements 104 V. DISCUSSION ..... 109 Acid Dissociation of Morphine • 109 Base-Titration of Morphine Free Base • . • • • . • • 110 Acid-Titration of Morphine Free Base • • • . • . • . • . 110 Metal Ion - Drug Interactions in Aqueoiz~ Sol utio1:1 • . • . 111 Ca - Morphine Interaction 111 Ps3~domorphine . • • . 112 Fe and Ag - Morphine Interactions . • • . 113 Reaction of Drugs in Concentrated Sulfuric Acid . • . • . • . 115 Color Reactions of Drugs in Concen- trated Sulfuric Acid • • . 118 Conclusions and Suggestions for Further Work . • . • • • . 123 A SELECTED BIBLIOGRAPHY . • . 128 v LIST OF TABLES Table Page I. The Spin and Natural Abundance of Some Common Nuclei • • • • . • . • • • • • 26 II. Compositions of Color Test Reagents and the Color Dev.eloped in Each Reaction 38 III. Results From CD-Base Titrations of Morphine Free Base at 285 and 300 nm • . • . 45 IV. CD-Acid Titration Data of Morphine Free Base at 285 nm . • . • . 49 V. Comparison of pK's 49 VI. CD Data of Morphine and Metal Interactions in Aqueous Solution . • . • . 60 VII. UV-Visible Data of Drug - Color Reactions, Immediately After Mixing • • • • . • 70 VIII. UV-Visible Data of Drug - Color Reactions, After 15 Minutes • . • • . • • . 71 IX. UV-Visible Data of Drug - Color Reactions, After 24 Hours • . • • . • . • . • · 76 x. CD Data of Drug - Color Reactions, Immediately After Mixing . 85 XI. CD Data of Drug - Reactions, After 15 Minutes 86 XII. CD Data of Drug - Reactions, After 24 Hours . 87 XIII. ESR Data of Morphine Sulfate - Color Reactions . • • . • . • . • . • • 98 XIV. ESR Data of Codeine - Color Reactions 99 XV. ESR Data of Heroin.HCl - Color Reactins 100 XVI. CD and UV-Visible Data of Drugs in Concentrated Sulfuric Acid .•• 101 vi Table Page XVII. CD and UV-Visible Data of Apomorphine - Color Reactions • • . • • • • • • • • 103 XVIII. CD and UV-Visible Data of Morphine Sulfate with Some Color Test Reagent . 103 XIX. 13c NMR Chemical Shifts of Morphine Sulfate in D20 . 108 vii LIST OF FIGURES Figure Page 1. Structure of Drugs: Morphine: R = R' = H, Codeine: R = ca 3 , R' = H, Heroin: R = RI = -8-CH .3 . •. • • • • . 7 2. The Glan-Thompson Prism, Showing the Two Resolved Plane Polarized Beams of Light . • • . 11 3. Plane Polarized Light Which Results From the Summation of the Two Circularly Polarized Com­ ponents. The Circular Vectors and Their Summa­ tions at 'Arly Point in (b) Are Represented By the Sine Wave In (a) • • • . • . • • . • • . • 13 4. Diagram (a) Illustrating the Angle of Rotation (a) Caused by Unequal Speed of Propagation for the Two Circularly Polarized Components Through a Circularly Birefringent Medium. Diagram (b) Showing the "Plain" and the "Anomalous" ORD Curve .• . .. • . • . • . 14 5. Elliptically Polarized Light Produced When nL>nR and EL> SR • . • • • • • • • • • • 16 6. Splitting of Energy Levels of an Electron in an Applied Magnetic Field, H. E1 and E~ are the Energies of the Spin States in Whicn the Magnetic Dipoles are Aligned Parallel and Anti-Parallel to the Applied Magnetic Field Respectively • • • • 20 7. Diagrams Showing Energy Levels, ESR Absorption Spectrum and the First Derivative of Absorption Intensity .• . • • . • . • • • • . • • • 23 8. Diagram Drawing Energy Levels, Transitions, Hyper­ fine Structures and Relative Intensity of Lines for Two Equivalent Nuclei with Nuclear Spin, I = 1/2 • • • . • • • • • • • • • • • • . 27 9. Diagram Drawing Energy Levels, Transitions, Hyper­ fine Structures and Relative Intensity of Lines for a Nucleus with Nuclear Spin, I = 1 28 viii Figure Page 10. The Relative Intensity of ESR Lines From the Pascal's Triangle . • . .•.•.•• 29 11. Isotropic CD Spectra of 2.5113 X 10-4 M Morphine Free Base Solution, (~-) Morphine Free Base in Distilled Water, (---) Morphine Free Base in 1 M NaOH, (-•-•-), Morphine Free Base in 1 M HCl . • . • . • • • . • . • 41 12. CD Spectra o f So 1 ut1ons. From Fe 3+ - Morp h'1ne Sulf a~e Reacti~~ at Different Mole Ratios of Morphine to Fe . • . • . • . • . • . 52 13. CD Spectra of Solutions Containing 1:1 Mole Ratio of Solid Morphine Sulfate to 1%, AgNO Solution Recorded at Different Time Intervafs 53 14. CD Spectra of Solutions Obtained from Ag+ Morphine Free Base Reactions After l Hour 55 15. The Proposed Molecular Structure of Pseudo- morphine . 56 16. CD Spectra of Pseudomorphine . 57 17. UV Spectra of Pseudomorphine . 58 18. UV Spectra of Drugs in Cone. H2so 4 . 62 19. UV Spectra of Drugs in Cone. H2so 4 . 63 20. UV-Visible Spectra of Morphine Sulfate (~-), Codeine (---), and Heroin HCl (-·-·- ) With Marquis Reagent (a) Immediately After Mixing (b) 15 Minutes Later •••••....•. 66 21. UV-Visible Spectra of Morphine Sulfate (~-), Codeine (---), and Heroin HCl <-·-·-) With Frohde Reagent • • . • . ~ 67 22. UV-Visible Spectra of Morphine Sulfate (~-), Codeine (---), and Heroin HCl (-·-•-) With Mecke Reagent . • . • . 68 23. UV-Visible Spectra of Morphine Sulfate (~-), Codeine (---), and Heroin HCl (-•-•-) With Mandelin Reagent • • • • . • . • • • . • 69 24. UV-Visible Spectra of Morphine Sulfate (~-), Codeine (---),and Heroin HCl (-·-•-)With Marquis Reagent Recorded After 24 Hours • . 72 ix Figure Page 25. UV-Visible Spectra of Morphine Sulfate (~-), Codeine (---), and Heroin HCl (-•-·-) With Frohde Reagent Recorded After 24 Hours 73 26. UV-Visible Spectra of Morphine Sulfate (~-), Codeine (---),and Heroin HCl <-·-•-) With Mecke Reagent Recorded After 24 Hours . • . 74 27. UV-Visible Spectra of Morphine Sulfate (~-), Codeine (---), and Heroin HCl (-•-•-) With Mandelin Reagent Recorded After 24 Hours • . • 75 28. CD Spectra of Morphine Sulfate (~-), Codeine (---), and Heroin HCl (-•-•-) With Marquis Reagent . • . • • • . • . • . • • • 77 29. CD Spectra of Morphine Sulfate (~-), Codeine (---),and Heroin HCl (-•-•-)With Erdman Reagent • . • • • . • 78 30. CD Spectra of Morphine Sulfate (~-), Codeine <---),and Heroin HCl (-•-•-)With Mandelin Reagent . • • • . • . • . 79 31. CD Spectra of Morphine Sulfate (~-), Codeine (---), and Heroin HCl (-•-•-) With Mecke Reagent • . • . • . • . • . • 80 32. CD Spectra of Morphine Sulfate (~-),Codeine (---), and Heroin HCl (-•-•-) . • . • 82 33. CD Spectra of Morphine Sulfate (~-),Codeine (---), and Heroin HCl (-•-•-) With Mandelin Reagent, After 24 Hours . • . • . • . 83 34. CD Spectra of Morphine Sulfate (~-),Codeine (---), and Heroin HCl (-•-•-) With Mecke Reagent, After 24 Hours . • . 84 35. ESR Spectra of Drugs - Marquis Color Reactions 89 36. ESR Spectra of Drugs - Erdman Color Reactions 90 37. ESR Spectra of Drugs - Mecke Color Reactions 91 38. ESR Spectra of Drugs - Mandelin Color Reactions 92 39. ESR Spectra of Drugs - Frohde Color Reactions 93 40. ESR Spectra of the Colored Mixtures 97 x Figure Page 41. 13c NMR Spectrum of Morphine Sulfate in o2o . 105 42. 13c NMR Spectra of Morphine Sulfate in Concentrated Sulfuric Acid . • . 106 43. Molecular Structure of Apomorphine and Apomorphine-o-Quinone • • . • 117 44. The Flow Chart Showing the Possible Inter­ mediates Formed in the Drug-Color Reactions 124 xi CHAPTER I INTRODUCTION
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