Investigation of Carbamazepine- Nicotinamide cocrystal solubility and dissolution by a UV imaging system PhD Thesis Ning Qiao This thesis is submitted in partial fulfilment of the requirements of De Montfort University for the award of Doctor of Philosophy April 2014 Faculty of Health and Life Sciences De Montfort University Leicester CONTENTS CONTENTS CONTENTS ................................................................................................................................... I DECLARATION ........................................................................................................................... v ABSTRACT .................................................................................................................................. vi ACKNOWLEDGEMENTS ......................................................................................................... vii PUBLICATIONS ........................................................................................................................ viii LIST OF FIGURES ....................................................................................................................... x LIST OF TABLES ...................................................................................................................... xiii ABBREVIATIONS ..................................................................................................................... xv Chapter 1 Introduction .................................................................................................................. 1 1.1 Research background .......................................................................................................... 1 1.2 Research aim and objectives ............................................................................................... 2 1.3 Thesis structure ................................................................................................................... 3 Chapter 2 Literature Review ......................................................................................................... 5 2.1 Chapter overview ................................................................................................................ 5 2.2 Cocrystal background review.............................................................................................. 5 2.2.1 Cocrystal definition ...................................................................................................... 5 2.2.2 Crystal engineering ...................................................................................................... 7 2.2.3 Pharmaceutical cocrystals design strategies ................................................................. 8 2.2.4 Cocrystal formation methods ....................................................................................... 9 2.2.5 Cocrystal characterisation techniques ........................................................................ 11 2.2.6 Physicochemical properties of cocrystals .................................................................. 13 2.3 Theoretical development on solubility prediction of pharmaceutical cocrystals .............. 17 2.3.1 Prediction of cocrystal solubility ................................................................................ 17 2.3.2 Cocrystal dissolution in surfactant solutions.............................................................. 22 2.3.3 Solution mediated phase transformation .................................................................... 25 2.4 Carbamazepine (CBZ) cocrystals studies ......................................................................... 29 2.4.1 CBZ introduction ....................................................................................................... 29 I CONTENTS 2.4.2 CBZ cocrystal studies ................................................................................................ 31 2.5 Introduction of pharmaceutical cocrystal coformers: nicotinamide and succinic acid ..... 35 2.6 Definitions of basics of pharmaceutical physical chemistry [143] ................................... 36 2.7 Chapter conclusions .......................................................................................................... 45 Chapter 3 Materials and Methods ............................................................................................... 46 3.1 Chapter overview .............................................................................................................. 46 3.2 Materials ........................................................................................................................... 47 3.3 Methods............................................................................................................................. 48 3.3.1 ActiPix SDI 300 UV imaging dissolution system ...................................................... 48 3.3.2 Enspectr R532 Raman spectrometry .......................................................................... 58 3.3.3 Infrared (IR) Spectroscopy ......................................................................................... 63 3.3.4 Ultraviolet–visible spectrometry (UV-Vis) ................................................................ 65 3.3.5 Differential scanner calorimetry (DSC) ..................................................................... 66 3.3.6 Thermal gravimetric analysis (TGA) ......................................................................... 67 3.3.7 High performance liquid chromatography (HPLC) ................................................... 68 3.3.8 Leica microscope ....................................................................................................... 71 3.3.9 Scanning electron microscope (SEM)[161] ............................................................... 71 3.3.10 CAM 200 surface tension meter .............................................................................. 72 3.3.11 Solubility test methods ............................................................................................. 74 3.4 Preparations....................................................................................................................... 75 3.4.1 Dissolution media preparation ................................................................................... 75 3.4.2 Test samples preparation ............................................................................................ 76 3.5 Chapter conclusions .......................................................................................................... 77 Chapter 4 Sample Characterisations ........................................................................................... 79 4.1 Chapter overview .............................................................................................................. 79 4.2 Materials and methods ...................................................................................................... 79 4.2.1 Materials .................................................................................................................... 79 4.2.2 Methods ...................................................................................................................... 79 4.3 Results ............................................................................................................................... 80 II CONTENTS 4.3.1 TGA analysis of CBZ DH .......................................................................................... 80 4.3.2 DSC analysis of test samples ..................................................................................... 80 4.3.3 IR spectroscopy analysis of CBZ-NIC cocrystal and CBZ-SUC cocrystal ............... 83 4.3.4 Raman spectroscopy analysis of CBZ-NIC cocrystal and CBZ-SUC cocrystal ........ 86 4.3.5 Molecular structures of CBZ-NIC cocrystal and CBZ-SUC cocrystal ...................... 91 4.4 Chapter conclusions .......................................................................................................... 92 Chapter 5 In Situ Monitoring of Carbamazepine-Nicotinamide Cocrystal Intrinsic Dissolution Behaviour .................................................................................................................................... 93 5.1 Chapter overview .............................................................................................................. 93 5.2 Materials and methods ...................................................................................................... 93 5.2.1 Materials .................................................................................................................... 93 5.2.2 Methods ...................................................................................................................... 94 5.3 Results ............................................................................................................................... 95 5.3.1 UV imaging dissolution tests ..................................................................................... 95 5.3.2 In situ monitoring of solid state transformation during dissolution using Raman spectroscopy ...................................................................................................................... 101 5.3.3 SEM ......................................................................................................................... 105 5.4 Discussion ......................................................................................................................