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Enhancement of the Rate of Solution of Relatively Insoluble Drugs from Solid-Solid Systems Prepared by Supercritical Fluid Technology

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Enhancement of the Rate of Solution of Relatively Insoluble Drugs from Solid-Solid Systems Prepared by Supercritical Fluid Technology ENHANCEMENT OF THE RATE OF SOLUTION OF RELATIVELY INSOLUBLE DRUGS FROM SOLID-SOLID SYSTEMS PREPARED BY SUPERCRITICAL FLUID TECHNOLOGY DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Carmen H. Ramirez, M.S. * * * * * The Ohio State University 2007 Dissertation Committee: Approved by Professor Sylvan G. Frank, Advisor Professor William L. Hayton Professor James T. Dalton ________________________ Advisor Professor Robert W. Curley Graduate Program in Pharmacy Copyright by Carmen H. Ramirez 2007 ABSTRACT Supercritical fluid technology, specifically the method of rapid expansion of supercritical solutions (RESS), has been used to prepare small particles consisting of solid solutions of a relatively insoluble drug and a water-soluble excipient. With an increasing number of relatively insoluble compounds being discovered, a general process for enhancing drug dissolution rates would assist formulation of these compounds for therapeutic use. Solid solutions could serve as a means for enhancing drug dissolution rates, since the drug is dispersed in a solid solvent in its smallest form, i.e., a molecule, prior to entering into solution. Therefore, solid solutions consisting of the relatively insoluble model drugs lidocaine or probucol and a water-soluble surfactant, poloxamers 407, 188, or 403 were prepared by RESS processing. Dissolution studies of these systems were performed and evaluated for their ability to enhance drug release rates. Furthermore, the mechanism by which solid solutions form in these systems was determined using differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. Scanning electron microscopy (SEM) was also used to study the surface characteristics of these particulate systems. ii Dissolution studies of these particles showed an enhanced rate of release of drug in the presence of poloxamer. This enhancement was due to the apparent formation of solid solutions. In addition, poloxamers served to improve the wettability of the drug particles by reducing the interfacial tension and contact angle at the solid/liquid interface, thereby helping enhance the dissolution rate of the drug. DSC of these particulate systems indicated the formation of solid solutions of drug and poloxamer with increasing proportion of poloxamer. At the point where all of the drug is molecularly dispersed forming a solid solution, no endotherm for the drug appears on the DSC thermogram. Therefore, in a phase diagram, linear extrapolation of the enthalpies of drug as functions of mole fraction to zero enthalpy could serve as a novel means for predicting the mole fraction of drug at which a solid solution should form. With the formation of solid solutions, hydrogen bonding occurred between the drug and poloxamer. This bonding was dependent on the polyoxyethylene chain length of the three poloxamers, i.e., where hydrogen bonding primarily occurs. Solid solutions formed for systems consisting of drug and poloxamers 407 or 188, which have similar polyoxyethylene lengths and hence similar amounts of available sites for bonding. Solid solutions however did not form for systems consisting of drug and poloxamer 403 since poloxamer 403 has approximately half the polyoxyethylene length of poloxamers 407 and 188. Lastly, SEM shows the formation of small particles that vary in appearance as functions of poloxamer concentration, i.e., from smooth spherical surfaces to structures similar to those of the drug alone. iii Dedicated to my mother, husband, and daughter iv ACKNOWLEDGMENTS I would like to give my special thanks to: My adviser, Dr. Sylvan G. Frank for his guidance, mentorship, passion and support of this project, for his dedication to my personal growth, and most importantly, his patience of which I am ever so grateful. Members of my committee, Dr. William Hayton, Dr. James Dalton, and Dr. Robert Curley for their suggestions and time. Dr. Arne Brodin for his intellectual contribution to this project and invaluable discussions. My labmates: Chao, Jessica, and Yong for their help and friendship. Kathy Kelley for her friendship, laughter, and putting up with my noise in the lab. My brother and sister and their families for their unending support and willingness to share our mother so that I could pursue my goals. My mother for leaving it all behind to come to Ohio. Thank you for your love, support, and undying faith in me. My husband David for your love, support, and especially your patience. My daughter Elena for your love, laughter, and smiles, which have kept me going. You are my inspiration. Always remember that no dream is ever too big. For all my friends and family who are not mentioned here, you do not go unrecognized by me. v VITA August 30, 1976 .................................................Born – Fort Worth, Texas 1998 ...................................................................B.S. Chemistry, University of North Texas 1999-2001 ..........................................................Graduate Research Associate The Ohio State University 2001-2004 ..........................................................Professor Sylvan G. Frank Graduate Fellow in Pharmaceutics 2004 ...................................................................M.S. Pharmaceutics, The Ohio State University PUBLICATIONS Research Publication 1. Hernandez, C.E. and Frank, S.G., “Enhancement Of The Rate Of Solution Of Relatively Insoluble Drugs From Solid-Solid Systems Prepared With Supercritical Fluid Technology.” Abstracts, AAPS Annual Meeting, Salt Lake City, UT, October, 2003 2. Hernandez, C.E. and Frank, S.G., “Enhancement Of The Rate Of Solution Of Relatively Insoluble Drugs From Solid-Solid Systems Prepared With Supercritical Fluid Technology.” 35th Pharmaceutics Graduate Student Research Meeting, Chicago, IL, June, 2003 FIELDS OF STUDY Major Field: Pharmacy Drug delivery, pharmaceutics, and pharmaceutical technologies vi TABLE OF CONTENTS Abstract ........................................................................................................ii Dedication.....................................................................................................iv Acknowledgements ......................................................................................v Vita ...............................................................................................................vi List of Tables ................................................................................................x List of Figures...............................................................................................xii Chapters: 1. Introduction..............................................................................................1 1.1 Solubility, dissolution, and bioavailability...........................................2 1.2 Solid dispersions ...............................................................................12 1.2.1 Definitions .................................................................................13 1.2.2 Methods of preparation .............................................................21 1.2.3 Characterization of solid dispersions ........................................24 1.2.4 Dissolution of drugs from solid dispersions...............................27 1.3 Supercritical fluid technology.............................................................30 1.3.1 Background...............................................................................30 1.3.2 Applications of supercritical fluid technology.............................37 1.3.3 Supercritical fluid processing methods......................................41 1.3.3.1 Rapid expansion of supercritical solutions (RESS)........41 1.3.3.2 Gas anti-solvent method (GAS) .....................................42 1.3.3.3 Other methods utilizing supercritical fluids.....................43 1.3.4 Applications of supercritical fluid technology in drug delivery .....................................................................................44 1.4 Objectives .........................................................................................52 2. Characterization of drug / surfactant systems consisting of relatively insoluble drug and various poloxamers formed by RESS processing...............................................................................53 2.1 Introduction .......................................................................................54 2.2 Purpose of the study .........................................................................58 2.3 Experimental .....................................................................................59 vii 2.3.1 Materials ...................................................................................59 2.3.1.1 Lidocaine .......................................................................59 2.3.1.2 Probucol.........................................................................61 2.3.1.3 Poloxamers 407, 188, and 403......................................63 2.3.2 Equipment.................................................................................66 2.3.3 Methods of particle formation....................................................69 2.3.3.1 Formation of drug / poloxamer 407, 188, or 403 particles by supercritical fluid processing.......................69 2.3.4 Methods of analysis ..................................................................73 2.3.4.1 Differential
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