Drug Release of Polymeric Pharmaceuticals

University of Massachusetts Amherst ScholarWorks@UMass Amherst Doctoral Dissertations 1896 - February 2014 1-1-1979 Drug release of polymeric pharmaceuticals/ Walter J. Deits University of Massachusetts Amherst Follow this and additional works at: https://scholarworks.umass.edu/dissertations_1 Recommended Citation Deits, Walter J., "Drug release of polymeric pharmaceuticals/" (1979). Doctoral Dissertations 1896 - February 2014. 640. https://scholarworks.umass.edu/dissertations_1/640 This Open Access Dissertation is brought to you for free and open access by ScholarWorks@UMass Amherst. It has been accepted for inclusion in Doctoral Dissertations 1896 - February 2014 by an authorized administrator of ScholarWorks@UMass Amherst. For more information, please contact [email protected]. DRUG RELEASE OF POLYMERIC PHARMACEUTICALS A Dissertation Presented By WALTER DEITS Submitted to the Graduate School of the University of Massachusetts in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY September 1979 Polymer Science and Engineering DRUG RELEASE OF POLYMERIC PHARMACEUTICALS A Dissertation Presented By WALTER DEITS Approved as to style and content by: (/hfiCipjt Otto Vogl, 'chairman of Committee F.E. Karasz , Member E.W* Westhead, Jr., Member F.E. Karasz, Acting Depart- ment Head Polymer Science & Engineering For my mother ACKNOWLEDGMENT The author would like to extend his sincerest gratitude to Professor Otto Vogl for his professional guidance and personal friendship throughout the course of this research. The efforts and helpful suggestions con- tributed by Professors Frank Karasz, Edward W. Westhead, Jr., and William MacKnight are also appreciated. The author would also like to thank his laboratory coworkers, particularly Dr. David A. Tirrell, Dr. L. Steven Corley and Mr. Steve Grossman, for their cooperation and friendship throughout the author's course of study. ABSTRACT Drug Release of Polymeric Pharmaceuticals (September 1979) Walter Deits B.S., San Diego State University Directed by: Professor Otto Vogl Several novel polymers containing selected monomers with known pharmaceutical activity as integral parts of the chain backbones were synthesized, and their hydrolytic stabilities examined, with the objective of determining the factors affecting the rate of release of the active agents from the polymer systems under conditions resembling those encountered in a physiological environment. Primaquine (8- (4-amino-l-methylbutylamino) -6-methoxy- quinoline) was found to be difficult to incorporate into the backbone of a polymer chain. This was shown to be due to an unequal reactivity between the primary aliphatic and the hindered secondary aromatic amino groups. Side reactions associated with the quinoline moiety were also shown to be a source of problems. Primaquine was incorporated into several polymers of moderate molecular weight by forming biuret linkages with the primary amino group from a reaction between the drug and a diisocyanate Bithionol (2,2'-thiobis(4,6-dichlorophenol)) was synthesized in 43% yield fro. 2 , 4-dichlorophenol and sulfur dichloride. A variety of bithionol polyesters, as well as poly (bithionol phenylphosphate), poly (bithionol phenyl- Phosphonate), and poly (bithionol phenylphosphinate ) were prepared from bithionol and various diacid chlorides, Phenyldichlorophosphate, phenyl phosphonicdichloride , and dichlorophenylphosphine, respectively. Reaction of bithionol with phosgene afforded a 40% yield of bithionol bischloroformate which was used to prepare a number of polycarbonates and polyurethanes from diols and diamines, respectively. The hydrolytic stability of selected polymers was examined at 37°C and pH 7.4. Solubility was found to be the most important factor influencing the rate of hydrolysis The polymers that were water soluble or at least water swellable were found to hydrolyze according to second-order kinetics and at a rate many times faster than polymers that were insoluble. The insoluble polymers were found to hydrolyze according to zero-order kinetics. The presence of hydrophilic polyoxyethylene segments was also found to enhance the rate of hydrolysis. V TABLE OF CONTENTS Page ACKNOWLEDGMENTS iii ABSTRACT . , ' LIST OF TABLES *. ' iv LIST OF FIGURES . ^ xii Chapter I. INTRODUCTION ^ I. Polymeric Pharmaceuticals and the Sustained Release of Biological Agents General Background '2 II. Preparation and Properties of Polymeric Pharmaceuticals and Sustained Release Formulations ^ A. Membrane encapsulated reservoir devices ^ B. Matrix devices ! ! ! 6 C. Reservoir devices without a membrane ^ D. * Erodible devices [ -j E. Chemical complexes F. Ionic polymers 21 G. Covalent compounds 13 III. Preparation and Properties of Polymeric Pharmaceuticals Incorporating Active Agents in the Main Chain 19 IV. Hydrolytic Degradation of Synthetic Polymers 24 V. Biological Degradation of Synthetic Polymers 31 VI. Biological Activities of Primaquine and Bithionol 34 A. Primaquine 34 B. Bithionol 39 VII. Preparation of Polymers From Hindered Bisphenols 43 II. EXPERIMENTAL SECTION 50 I. Materials 50 II. Purification of Solvents and Reagents 51 vi ' Chapter Page III Polymerization of Primaquine A. Isolation of primaquine B. Reaction of * primaquine * wiih ' tional dif in^- intermediates using one-steP polymerization techniques ^ C. Synthesis of phthalimido ^ primaquine * D. ' Preparation of ' primaquine ' biuret polymers E. Preparation of prim^quiAe-sub^tituted polyepichlorohydrin -LLutea IV. Preparation of * Bithionol aAd ' * Polymers Bithiinol A. Bithionol B. ' Bithionol bischloroformate and " ' * bithionol carbonate bischloroformate . 66 C. Bithionol polycarbonate D. Bithionol alternating "copolycarbonates E. * Bithionol/polyethylen4 glycol alternating copolycarbonates . -75 ^* terpolycarbonates* containing PEG^4000^ 77 G. Bithionol alternating copolyurethanes 81 H. Bithionol copolyurethanes containing PEG 4000 ^ 84 I. Bithionol polyesters ....!!!.* 87 J. Bithionol polymers containing phosphorous ^-^ V. Preparation of Hindered Bisphenol Polyesters 92 A. Poly [4,4' -methylenebis(6-tert-butyl- o-cresol) sebacate] 2 92 B. • Poly [2 , -methylenebis (6-tert-butyl- p-cresol) sebacate] 93 C. Poly[4,4'-thiobis (6-tert-butyl-m-' cresol) sebacate] 94 D. Poly[4,4'-thiobis{6-tert-butyl-o-* cresol) sebacate] 94 VI. Measurement of the Rates of Hydrolysis* of Bithionol Polymers 95 A. Preparation of buffer solutions ... 95 B. Preparation of polymer solutions . 95 C. Determination of polymer concen- trations 95 vii * Chapter Page ^' 0^?^^''^^^°'' °^ bithionol absorbtion calibration curve E. * Measurement of the rate'of release ' °f bithionol from ..^^ polymer solutions-L^nt, 97 VII. Measurements . y/ 97 III. RESULTS AND DISCUSSION 99 I. Objectives II. Polymerization of PrimaquiAe* ! |uu-, A. Isolation of ' * • • primaquine . B. Reaction of primaquine with difunc-* tional intermediates using one-step polymerization techniques .... iqI C. Attempted polymerization of primaquine using a multi-step polymerization scheme 106 D. Preparation of primaquine biuret polymers 115 E. Preparation of primaquine-substituted polyepichlorohydrin ]^22 III. Preparation of Bithionol and Bithiinil* Polymers ^23 A. Introduction .*!!!.* 123 B. Preparation of bithionol ...... 124 C. Preparation of bithionol bischloro-' formate and bithionol carbonate bischlorof ormate j^24 D. Preparation of bithionol polycarbonate -^21 E. Preparation of bithionol alternating copolycarbonates I37 F. Preparation of bi thionol/polyethylene glycol alternating copolycarbonates . 142 G. Preparation of bithionol terpolycarbonates containing PEG 4000 . 144 H. Preparation of bithionol alternating copolyurethanes I47 I. Preparation of bithionol copolyurethanes containing PEG 4000 .... 152 J. Preparation of bithionol polyesters . 154 K. Preparation of bithionol polymers containing phosphorous 162 IV. Preparation of Polymers from Hindered Bisphenols 167 V. Measurement of the Rates of Hydrolysis of Bithionol Polymers 173 viii Chapter Page VI. Conclusions and Further Work J. y j_ REFERENCES * ' V 194 APPENDIX A. PROTON MAGNETIC RESONANCE SPECTRA . 203 APPENDIX B. INFRARED SPECTRA 217 ix — * ' LIST OF TABLES Table Page 1. Some Commercial Controlled Products Release ^' Physioiogiiai En;i;o;m;n; PolymerPof^""^ °n on Properties . 3. Transition * Temperature of * ' from Polycarbonates'i-^onares Bisphenols . 4. Polymer Melt * Temperature^ if p;i;i;ophth;i;t;si^^sopntnaiates from Substituted Phthaleins 5. Preparation ' ' of Primaquine * Biuret * P^limir; A 6. * " Preparation of Primaquine-Substituted * Polyepichlorohydrin 7. Solubility of Polymers'i^ Aqiieiu; ' * Soiuiiin' * It ^PP^^^^nce Of Reaction Mixtures * Phthalimido Containing Primaquine and Acid Chlorides Reaction * m °5 Mixtures Containing ' Sv"^"Quinolme and Acid Chlorides 10. Preparation of Bithionol Polycarbonate ' At 11. Preparation * * of Bithionol Alternating Co-* polycarbonates from Bithionol Bischloro- formate and Diol 12. Preparation of Bithionol/Polyethylene * Alternating Glycol* Copolycarbonates . * 140 13. Preparation of * Bithionol Terpolycarbonitis * Containing PEG 4000 -..g 14. Preparation of Bithionol Alternating ' Co- polyurethanes from Bithionol Bischloro- formate and Diamine -j^^g 15. Preparation of Bithionol Copolyurethanes Containing PEG 4000 ^^55 16. Preparation of Bithionol Polyesters from* Bithionol and Acid Chloride I59 17. Preparation of Bithionol Polyesters Influence of Polymerization Technique .... 161 18. Preparation of Polymers from Hindered

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