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Pharmaceutical Powder Compressibility – a Science-Based Approach

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Pharmaceutical Powder Compressibility – a Science-Based Approach Pharmaceutical powder compressibility – a science-based approach Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Nicolaos D.Gentis aus Egrigoros (Chios) Griechenland Oberkulm (AG) Schweiz Basel, 2012 Approval Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Matthias Hamburger und PD Dr. Gabriele Betz und Prof. Dr. Thierry F. Vandamme Basel, den 21. Februar 2012 Prof. Dr. Martin Spiess Dekan 2 Dedicated to my parents with love, appreciation and respect 3 Σωκράτης ―I know one thing, that I know nothing‖ Socrates c. 469 BC – 399 BC 4 Acknowledgements The work for this PhD thesis was carried out in the Industrial Pharmacy Lab, Department of Pharmaceutical Sciences, University of Basel and at the facility of Natoli Engineering Inc. in Saint Louis, Missouri (USA). I would like to express my appreciation and sincere gratefulness to PD Dr. Gabriele Betz for giving me the opportunity to do a PhD under her excellent supervision with essential, continuous support, guidance and brilliant, positive motivation. I would like to thank Prof. Dr. Matthias Hamburger for accepting to be my Faculty Responsible and for the support. My appreciation goes also to Prof. Dr. Thierry F. Vandamme for accepting to assume the co-referencing of this PhD thesis. At this point I would like to thank all former Industrial Pharmacy Research Group members for the unique support and for the great, crazy working atmosphere in the laboratory. Especially I would like to thank Mr. Branko Z. Vranic for his great collaboration and support in the research work of project 2 in this thesis. Additionally, I thank Branko for a great support in the teaching obligations (Physical Chemistry classes) and for the great friendship. A special appreciation goes also to Dr. Felicia Flicker, Dr. Muhanned Saeed and Dr. Sameh Abdel-Hamid for their great collaboration and support during the last three years. During my PhD - internship stay at Natoli Engineering I had the chance meet and to work together with numerous great people. Namely, I would like to thank Dale Natoli, Dr. Chuck Kettler and his dear wife Julie, Vince and Tammy Natoli, Cammi Grittini, Kim Williams, Dave Holleran and my dear friend Stephen Natoli for their big support and for making my time in the States to be unforgettable. Also the people outside the company, who supported me a lot deserve a big ―Thank you!‖. Namely, Pater Joseph and his son John Strzelecki, John Gialouris and Mr. Isidoros Spanos with family for their hospitality. 5 For me, this chapter of the thesis is really essential, since it gives me the opportunity to thank my close family and friends for all their support during the last years and for their company in really happy but also in difficult moments of life: Mrs. Anna-Ruth Schlapbach for her help and guidance in every up and down of my life, my dear ―koumpari‖ Mrs. Iliàs Charlafti, Mr. Polychronis Dimitrakis and of course Mrs. Stella Christou, my dear godchildren Andromeda and Eleni Irini for enriching my life, my loved godparents Notis and Sevasti Michelis, my cousins Sotiria Tsangeou-Tsichla and Giannis Datseris with their families, my dear friend Georgios Nikolaids with family and also family Kasapidis for all their support. A special word of appreciation goes to my dearest brother Georgios for his company and big support through my life and to his family. The biggest gratitude I have to express to my parents: Thank you for being the most wonderful parents one can have and for your support and love throughout my whole life! 6 Table of Contents Approval .................................................................................................................................2 Acknowledgements ................................................................................................................5 Table of Contents ...................................................................................................................7 List of Figures ....................................................................................................................... 11 List of Tables ........................................................................................................................ 13 List of Original Publications .................................................................................................. 14 List of Abbreviations ............................................................................................................. 15 Thesis Abstract .................................................................................................................... 17 Background ...................................................................................................................... 17 Objective ........................................................................................................................... 17 Materials and Methods ...................................................................................................... 17 Results and Discussion ..................................................................................................... 18 Conclusion ........................................................................................................................ 18 Theoretical background ........................................................................................................ 19 Material ............................................................................................................................. 19 Cellulose ....................................................................................................................... 19 Microcrystalline Cellulose: Polymorphism and its influence on the compaction ............. 22 Paracetamol .................................................................................................................. 23 Mefenamic acid ............................................................................................................. 25 Starch ............................................................................................................................ 27 Calciumhydrogenphosphate .......................................................................................... 30 Pharmaceutical powder: Analytical investigation ............................................................... 32 Powder sampling ........................................................................................................... 33 Pycnometry ................................................................................................................... 34 Particle size measurement ............................................................................................ 39 7 Scientific term ―density‖ ................................................................................................. 41 Powder compaction ....................................................................................................... 42 Powder behaviour under pressure and its predictabiliy .................................................. 47 Instrumented tablet presses .......................................................................................... 57 Compaction simulators .................................................................................................. 62 Near-Infrared Spectroscopy .......................................................................................... 68 Research Project 1: Compressibility of binary powder formulations: Investigation and evaluation with compaction equations....................................................... 75 Abstract ............................................................................................................................ 75 Introduction ....................................................................................................................... 76 Research aim ................................................................................................................... 81 Theoretical section ............................................................................................................ 82 Heckel- Plot ................................................................................................................... 82 Modified Heckel- Plot .................................................................................................... 83 Leuenberger equation ................................................................................................... 84 Binary mixtures: compaction properties and percolation theory ..................................... 85 Materials and Methods ...................................................................................................... 87 Materials ....................................................................................................................... 87 True density measurement of pure materials ................................................................. 87 Density calculation of powder mixtures .......................................................................... 87 Particle size measurement ............................................................................................ 87 Design of powder formulations .....................................................................................
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