Browsing Theses by Subject "Nanocrystals"
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Preparation and stability of organic nanocrystals. Experimental and molecular simulation studies.A major challenge affecting the likelihood of a new drug reaching the market is poor oral bioavailability derived from low aqueous solubility. Nanocrystals are rapidly becoming a platform technology to address poor solubility issues, although several challenges including stabilisation and control of particle size distribution for nanosuspensions still need to be addressed. The aim of this study was to revisit the simplest approach of re-precipitation and to identify the critical parameters, including the effect of different stabilisers as well as process conditions. We utilised a combined approach of both experiments and molecular modelling and simulation, not only to determine the optimum parameters but also to gain mechanistic insight. The experimental studies utilised three rather distinct, relatively insoluble drugs, the hypoglycaemic glibenclamide, the anti-inflammatory ibuprofen, and the anti-malarial artemisinin. The choice of crystal growth inhibitors/stabilizers was found to be critical and specific for each drug. The effect of the process variables, temperature, stirring rate, and the solute solution infusion rate into the anti-solvent, was rationalized in terms of how these factors influence the local supersaturation attained at the earliest stages of precipitation. Coarse grained simulation of antisolvent crystallisation confirmed the accepted two step mechanism of nucleation at high supersaturation which involves aggregation of solute particles followed by nucleation. Recovery of nanocrystals from nanosuspensions is also a technical challenge. A novel approach involving the use of carrier particles to recovery the nanocrystals was developed and shown to be able to recover more than 90% of the drug nanocrystals. The phase stability of nanocrystals along with bulk crystals for the model compound glycine was explored using molecular dynamics simulation. The simulations were consistent with experimental data, a highlight being the ¿ phase transforming to the ¿ phase at temperature >400K and 20kbar respectively, as expected. Nanocrystals of ¿, ¿ and ¿ glycine, however did not show any phase transformation at high temperature. In summary the study demonstrates that standard crystallization technology is effective in producing nanocrystals with the primary challenge being physico-chemical (rather than mechanical), involving the identification of molecule-specific crystal growth inhibitors and/or stabilizers. The developed nanocrystal recovery method should enable the production of nanocrystals-based solid dosage forms. The molecular simulation studies reveal that crystal-crystal phase transformations can be predicted for hydrogen-bonded systems.