A High-pressure Vibrational Spectroscopie Study of Polymorphism in Steroids: Progesterone and Spironolactone BY Gisia L. Pisegna A thesis submitted to the Faculty of Graduate Studies and Research of McGill University in partial fulfiilntent of the requirements for the degree of Master of Science Novernber 1999 Departrnent of Chemistry McGill University Montréal, Québec, Canada "~isiaL. Pisegna üibîiothèque nationale du Canada Acquisitions and Acquisitions et BiMiographic Services senrices bibliographiques The author has grantecl a non- L'auteur a accordé une licence non exclusive licence dowing the exclusive permettant à la National Lihuy of Canada to Bibliothèque nationale du Canada de reprodoce, Ioan, distribute or seil reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de mic~che/nlm,de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts lkom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent 'être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Abstract The effect of high extemal pressures on the vibrational (IR and Raman) spectra of the polymorphs of progestemne and spironolactone has been examined. The high pressures were achieved with the aid of a diamond-anvil ce11 between ambient pressure and 50 kbar (-50,000 atm). The pressure dependences of selected vibrational modes were obtained. Wavenumber vs. pressure plots were used to determine the dv/dp values. Progesterone exists in two polymorphic forms and Form 11 is more thermodynamically sensitive than is that of Form 1. Form 1 exhibited a pressure-induced structural transition at - 20 kbar, whereas Form II exhibited a phase transition at - 15 kbar. Spironolactone aiso exists in two polymorphic forms, where Form II is more thermodynamically sensitive. Form 1 exhibited a structural transition at - 16 kbar and Forrn 11 at - 12 kbar. L'effet de hautes pressions externes sur les spectres vibrationnels (InfraRouge et Raman) des polymorphes de la progestérone et de la pirolactone a et6 étudié. Les hautes pressions, pouvant aller de la pression ambiante jusqu'à 50 kbar (-50,000 atm), ont été atteintes à l'aide d'une cellule à enclumes de diamant. Les variations de certains modes vibrationnels sélectionnés au préaiable, ont été enregistrés. Les courbes des nombres d'onde en fonction de la pression ont été utilisées pour déterminer les valeurs de dv/dp. La progestérone existe sous deux formes polyrnorphiques et la Forme JI est plus thermodynamiquement sensible que la Forme 1. La Forme I possède une transition structurelle induite par la pression à -20 kbar alors que la Forme 11 montre une transition de phase B - 15 kbar. La spirolactone existe également sous deux formes polymorphiques et la Forme II est plus thermodynamiquement sensible. La Forme 1possède une transition structurelle à - 16 kbar et la Forme II à - 12 kbar. 1 would fust like to thank my supervisor, Professor Ian Butler, for his support, encouragement and enthusiasm throughout the course of this work. 1 would also like to acknowledge: Stephanie Warner for her endless support, encouragement and fkiendship. Man y thanks ! Dr. Zen Hua Xu, Clare Edwards, Heather Gass and my other lab #335 colleagues for their support. encouragement and friendship; Shane Pawsey for his help @SC) and for his friendship. as well as my friends from Otto Maass who made Montreal enjoyable; Pierre Lesté-Lasserre for help with the translation of the abstract and his friendship ; Michel Boulay for technical assistance with the IR and Raman spectrometers and Dr. Anne-Marie Lebuis for the 'numerous' X-ray patterns and her support; Ms. Renée Charon and dl the other office staff for taking care of the administration, and My family and friends for their endless support and encouragement. Note on Units The following units have been used in this thesis for historical reasons. Their definitions and SI equivalents are given below: Ph ysical Qumtity Symbol SI Units Units Used wavenumber v m" cm-' (= 100 m") pressure P Pa (N m-2) kbar (= 108 Pa) force constant k N m" dyne cm-' (= 10.' N m-') bond length r m A (= IO-'' m) ce11 constants & b, c m A (= 10-'O m) In the text of this thesis, the unit of vibrational wavenurnber is often referred to as the vibrational frequency (v). These quantities are dirvctly proportional to one another, v = c ;, where c is the speed of light. List of Abbreviations The followiny abbreviations have ken used in ihis thesis: Atmosphere atm Diamond-anvil ce11 DAC Infrared IR NuchMagnetic Resonance NMFt Differential Scanning Calorimetry DSC Potassium Bromide KBr vii Table of Contents .. Abstract ......................................................................................... ..il ... Resume ........................................................................................... 111 Acknow ledgments .............................................................................. iv Note on Units ..................................................................................... v List of Abbreviations........................................................................... vi Chapter 1 Introduction .................................................................... 1 1.1 High-pressure DAC Technique ...............................................2 1.2 Infrared and Raman Spectroscopy ...........................................5 1.3 References....................................................................... 7 Chapter 2 Polymorphisrn in the Pharmaceutid Industry 2.1 Introduction ...................................................................... 8 2.2 Applications of Polymorphism in the Pharmaceutical Industry .......... 9 2.3 Methods Used to Identify Polyrnorphs .................................... 10 2.4 FAQ's in the Identification of Polyrnorphs ................................ 13 2.5 Polymorphism of Certain Dmgs and Steroids............................ 13 2.6 References.................................................................... -20 Chapter 3 Experimental Section 3.1 High-pressure Micro-infrared Spectra..................................... 2 3.2 High-pressure Micro-Raman Spectra ...................................... 24 3 -3 Data Error Anal ysis ........................................................... 25 3.4 Preparation of Progesterone - Forms 1 and II ............................. 26 3.5 Preparation of Spironolactone - Forms 1 and lI ...........................39 3.6 References .................................................................... -49 Chapter 4 High-pressure Study of Progesterone and Polymorphism 4.1 Introduction ................................................................. -30 4.2 Polymorphism of Progesterone ............................................ -50 4.3 Results and Discussion ..................................................... -53 4.3.1 IR and Rarnan Pressure Studies of Form I ........................ 57 4.3.2 IR and Rarnan Pressure Studies of Fonn II .....................-69 4.4 Conclusions .................................................................... 79 4.5 References .................................................................... -81 Chapter 5 High-pressure Study of Spironolactone and Polymorphism 5.1 Introduction .................................................................... 82 5.2 Spironolactone and Polymorphism ....................................... -33 5.3 Results and Discussion ..................................................... -85 5.3.1 IR and Raman Pressure Studies of Form I ........................ 93 5.3.2 IR and Raman Pressure Studies of Form I1 ..................... 108 5.4 Conclusions ................................................................... 119 5.5 References ................................................................... -121 Chapter 6 Conclusions and Future Suggestions ................................... 122 6.1 References ................................................................... -125 Chapter 1 Introduction Polymorphism is a problem of particular importance to the pharmaceutical industry. Different polymorphs of a dnig can have different dissolution rates, which in turn cm affect bioavailability [1,2]. Much work has been done on the thermodynarnic properties of various pol ymorphs, main1y temperature studies, to investigate the relationships between the different forms. Numerous drugs such as, barbiturates, steroids and antihistarnines exhibit poiymorphism [1,2]. Progesterone and spironolactone, Figure 1.1, are the two steroids of focus in this thesis as little has been reported on the physicochemical properties of their poiymorphic forms, which will facilitate clarification of the inter-relationship between each forrn. Figure 1.1 Chernical structures of a) pmgesterone and b) sphnolactone. The overail objective of the research project was to provide information on the effect of high-pressure and other relevant properties of the steroids on their different polymorphic States. The use of the diamond-anvil cell, DAC, has become a popular approach for investigating materials under high pressure [3]. DACs have found their way into many fields of study, such as Chemistry, Physics, Geology, Biochemistry and Forensic Science. If certain polymorphs