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Ciprofloxacin (CIP) can exist in two different forms: the zwitterion and the unionized form. While the crystal structure of each has been described independently, the ability of CIP to transform from one to the other in the solid state has not been described. The crystal structures of unionized and zwitterionic CIP were therefore compared using computational methods, including their packing arrangement, hydrogen bonding, packing energy, intermolecular potentials and HOMO/LUMO energy gap. The pure amorphous form of CIP has also never been prepared or studied. Ball milling, cryomilling and spray drying were used in this study to prepare partially and fully amorphous CIP for the first time. The physical characteristics were examined by PXRD, FTIR and DSC. CIP proved to be very difficult to amorphize, and only spray drying in pure water resulted in a fully amorphous product. It was discovered that while most processing methods resulted in the more stable zwitterionic form of the drug, spray drying in an ethanol/water mixture produced the unionized form. The zwitterion was found to convert to the unionized form upon heating to its melting point, whereas the reverse transformation occurred when unionized CIP was exposed to high humidity. This study thus provides insight into the proton transfer which can occur in a zwitterionic drug in the solid state, and the resultant changes to its crystal structure. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 Abstract Ciprofloxacin (CIP) can exist in two different forms: the zwitterion and the unionized form.While the crystal structure of each has been described independently, the ability of CIP to transform from one to the other in the solid state has not been described. The crystal structures of unionized and zwitterionic CIP were therefore compared using computational methods, including their packing arrangement, hydrogen bonding, packing energy, intermolecular potentials and HOMO/LUMO energy gap. The pure amorphous form of this drug has also never been prepared or studied. Ball milling, cryomilling and spray drying were used in this study to prepare partially and fully amorphous CIP for the first time. The physical characteristics, and in particular ionization state, of these samples were examined by PXRD, FTIR and DSC. Analysis of the crystal packing of unionized and zwitterionic CIP revealed that the presence of ionic interactions between the charged groups of the latter results in a denser and more stable crystal lattice. A greater HOMO/LUMO energy gap was also calculated for this sample, confirming its lower reactivity. CIP proved to be very difficult to amo...

Itraconazole (ITR) is an antifungal drug with a limited bioavailability due to its poor aqueous solubility. In this study, ITR was used to investigate the impact of nanonisation and solid state change on drug's apparent solubility and dissolution. A bottom up approach to the production of amorphous ITR nanoparticles (NPs), composed of 100% drug, with a particle diameter below

10The fabrication of drug nanoparticles (NPs) with process-mediated tunable properties and 11 performances continues to grow rapidly during the last decades. This study investigates the 12 synthesis and phase tuning of nanoparticulate itraconazole (ITR) mesophases using quasi 13 nanoemulsion precipitation from acetone/water systems to seek out an alternative pathway 14 to the nucleation-based NP formation. ITR liquid crystalline (LC) phases were formed and 15 nematic-smectic mesomorphism was achieved via controlling solvent:antisolvent 16 temperature difference (ΔTS:AS). The use of ΔTS:AS=49.5 °C was associated with a nematic 17 assembly, while intercalated smectic A layering was observed at ΔTS:AS=0 °C, with both 18 phases confined in the nanospheres at room temperature. The quasi emulsion system has 19 not been investigated at the nanoscale before and in contrary to the microscale, quasi 20 nanoemulsion was observed over the solvent:antisolvent viscosity ratios of 1:7 to 1:1.4. 21Poly(acrylic acid) in the solvent phase exhibited a concentration dependent interaction when 22 ITR formed NPs. This nanodroplet-based approach enabled the preparation of a stable ITR 23 nanodispersion using Poloxamer 407 at 80 °C, which was unachievable before using 24 precipitation via nucleation. Findings of this work lay groundwork in terms of rationalised 25 molecular assembly as a tool in designing pharmaceutical LC NPs with tailored properties. 26 27

Common characterization techniques used to detect crystallinity in amorphous solid dispersions (ASD) typically have detection or quantification limits on the order of 1%. Herein, an amorphous solid dispersion of indomethacin and polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA) produced by hot melt extrusion was determined to be amorphous by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). However, through the use of transmission electron microscopy (TEM), residual crystals of two populations were identified: single crystals mid-dissolution (<100 nm) and nanocrystalline domains of 5-10 nm in size. Both domain types were observed to contain a high defect density. Polarized light microscopy (PLM) and scanning electron microscopy (SEM) techniques supplement these findings by corroborating crystallinity. The use of high resolution analytical techniques to identify and characterize residual crystallinity is considered an important first step to understanding the significance of these residual crystalline populations to ASD performance attributes.