Nanoseeds for pharmaceutical batch crystallisation
Creators: name: Hayles-Hahn, Cameka
Publisher: name: Imperial College London
Year: 2013

description: Homogeneous seed size and shape irregularities in batch crystallisation processes lead to variations in the crystal size distribution and crystal shape of active pharmaceutical ingredients (APIs). This thesis presents an extensive study into the tailoring of heterogeneous seeds to obtain reproducible mean crystal sizes and narrow crystal size distribution characteristics of the model product API paracetamol. Model heterogeneous seeds are primarily silica, and secondary seeds are zinc oxide and titanium dioxide. Synthesised silica seeds prepared according to the Stӧber protocol were compared with purchased manufactured silica seeds. Characterisation techniques including light scattering, nitrogen sorption and zeta potential amongst others were used to confirm the physical and chemical characteristics of the heterogeneous seeds. Monodispersed product crystal size distribution was achieved with the purchased silica seeds 7nm to 1µm; with the microporous synthesised silica seeds; with the functionalised seeds and with the Janus functionalised seeds. All comparisons were made with respect to an unseeded control batch. The synthesised mesoporous silica seeds when used at loads greater than 0.50wt.% resulted in broad crystal size distributions. The synthesised mesoporous silica seeds demonstrate that when a broad pore size distribution is present, a detrimental effect on crystal size distribution control occurs. The synthesised microporous heterogeneous seeds with pore sizes less than 2nm lead to the greatest reduction in the mean crystal size out of all the silica seeds. Monodispersity of the crystal size distribution is shown to be independent of the functionality of the seeds investigated. The amine, methyl and fluoro functionalised seeds facilitate the growth of monodispersed product batch sizes with mean crystal sizes in the range of 92-200µm. A “cut-off” fluoro functionalised seed size was observed at 1µm; where mean crystal sizes larger than 210µm were obtained. Here the competition between the paracetamol solute adsorption and electrostatic repulsions of the seed functionality is related to the product mean crystal size. An elongation of the primary paracetamol crystals was achieved with the synthesised mesoporous silica seeds, the methyl functionalised seeds and also with the commercially manufactured titanium dioxide seeds. Crystal growth inhibitions parallel to the pore width is one explanation for the effects of the mesoporous seeds. Significant agglomeration of the product crystals resulted from seed loads in the excess of 1.00wt.% of the purchased silica seeds, the synthesised mesoporous seeds, the fluoro functionalised seeds and in the presence of the synthesised zinc oxide seeds. These findings suggest that the seed hydrophilicity or the electronegativity exacerbate the agglomeration prone compound. Solution profile control close to the solubility curve was achieved with the synthesised mesoporous silica seeds and 0.50wt.% titanium dioxide seeds. The significance of the effect of hydrophobicity and local cluster entrapment of the heterogeneous seeds is investigated. In conclusion, the heterogeneous seed physical and chemical characteristics are found to play a similar role in determining the product mean crystal size, size distribution and crystal shape characteristics from batch crystallisation processes. The findings provide a framework for identifying potential key seed properties that can improve the quality and efficiency of batch crystallisation processes of APIs.