Preparation, stabilisation and isolation of drug nanoparticles for improved bioavailability

In this thesis, nanosuspensions of two hydrophobic active pharmaceutical ingredient compounds, mefenamic acid (MEF) and dalcetrapib (DCP) have been prepared using an antisolvent precipitation method (Chapter III and V, respectively). Variation of process parameters such as concentration, temperature, stirring rate or antisolvent to solvent ratio allowed for particle size reduction into the low micron (MEF, 0.25 µm – 3.05 µm) or nano (DCP, ~430 nm) size range. However, the suspensions of the prepared particles of both compounds were highly unstable and formed larger micron-sized agglomerates over time. A method of introducing different additives at different times during the process, i.e. stepwise addition of additives has been developed to improve the formation and stability of MEF nanocrystals (Chapter III). From the eight surfactant and polymeric additives evaluated to produce nanoparticles in suspension, the most effective additive was sodium docusate (DOSS). When DOSS was present initially in the system, nanoparticles, ~312 nm in size, were generated. However, the particle size was not stable but increased to ~788 nm after 80 minutes in suspension associated with a polymorphic transformation. Combining the initial use of DOSS with the subsequent addition of hydroxypropyl methylcellulose allowed for the production of a suspension of MEF nanocrystals (~317 nm) with improved stability. The size of the crystals did not change in the first two hours and only increased to ~365 nm after 18 hours. The interaction of hydroxypropyl methylcellulose with MEF particles delayed polymorphic transformation by inhibiting nucleation and/or growth of the stable MEF polymorph. The hypothesis that the reduction of the size of MEF nanocrystals in the presence of DOSS is due to nucleation promotion by the additive, a phenomenon rarely captured experimentally, was studied by performing a series of induction time experiments under moderate supersaturations, varying the solvent composition and the concentration of DOSS (Chapter IV). In 40 % dimethylacetamide – 60 % water and in the presence of DOSS (at concentrations of 0.1 mg/mL and 0.2 mg/mL), classical nucleation theory reveals that the pre-exponential factor (A) increases by approximately 50 % while the interfacial energy is essentially uninfluenced. It is also found that the crystal growth rate becomes higher in the presence of DOSS. It is thus hypothesized that transport and desolvation of MEF molecules is facilitated in the presence of DOSS. With increasing amount of dimethylacetamide in the binary solvent mixture, the influence of DOSS appears to decrease. As an alternative to using soluble additives, DCP nanoparticles have been stabilized and formulated as solid nanocomposites on larger montmorillonite (MMT) carrier particles. This method combines the very high dissolution rate of the DCP nanoparticles with the simple solid-liquid separation and drying of the MMT composite microparticles (Chapter V). The solid state nanocomposite microparticles demonstrated fast dissolution up to a drug loading of 20.9 % and the formulation was stable for a minimum of 10 weeks in the solid state. No surface functionalisation of the MMT particles was needed and the presence of soluble surfactant and polymeric additives even hindered the preparation of the composite particles, decreasing nanoparticle attachment to the carrier particles and thus limiting the maximum achievable drug loading.