The production, characterisation, stabilization and isolation of azole anti-fungal nanoparticles

Abstract

In this work, the effect of stabilizer choice and concentration was investigated on nanoparticle (NP) stability over time. Three different BCS class II active pharmaceutical ingredients (APIs): itraconazole (ITR), ketoconazole (KETO) and posaconazole (POS) were chosen due to their poor aqueous solubility and closely related chemical structures. Polyethylene glycol (PEG), polyethylene glycol methyl ether (MPEG) and polyethylene glycol dimethyl ether (DMPEG) with a molecular weight of 2,000 Dalton were included as stabilizers. NPs were formed in situ using an anti-solvent addition, bottom up method at 25 ?C. Colloidal stability was monitored using dynamic light scattering (DLS), accompanied by morphological examination of the NPs using scanning electron microscopy (SEM). Kinetic modelling indicated nanoparticle growth is driven by Ostwald ripening (OR). The presence of DMPEG caused OR growth to become an interface controlled process following a parabola trend. DMPEG encouraged OR for POS NPs whilst driving the crystallisation process. The rate of OR appeared to be inherent of the crystallisation pathway by which these APIs proceeded. Crystallisation mechanisms were API, stabilizer type and concentration dependent. DLS can be considered suitable as an initial systematic screening method for stabilizer selection, aiding the pharmaceutical scientist in the optimisation of nano-formulations. Sample complexity and polydispersity presents challenges surrounding particle size measurements for nanoparticles (NPs). To ensure the delivery of high quality products to the marketplace it is imperative that this task is performed with the greatest accuracy and certainty. For this reason, particle sizing via more than one technique is critical to the success of the formulation process. Dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA) are techniques that size particles based on their Brownian motion in liquid medium. However, each technique has advantages and disadvantages associated with its application. DLS and NTA were compared in a critical manner. NPs were formed using ITR, KETO and POS, using an anti-solvent addition, bottom up method. The impact of PEG, MPEG and DMPEG as stabilizers, was assessed using these two particle sizing techniques. Mie light scattering theory was successfully used to explain the relationship between material composition and particle scattering power. A change in material refractive index, associated with an amorphous to crystalline solid state transformation, was predominantly responsible for the observed change in the light scattering power of POS nano-dispersions. The innovative application of NTA for the live tracking of these physical processes was explored for the first time. This novel finding can serve to deepen our understanding of the dynamic crystallisation pathway undertaken by a NP. Numerous techniques were coupled in an attempt to gain greater understanding surrounding the nature of the relationship between drug polymer interactions and their impact upon NP stabilization. The assembly of polymer molecules onto ITR particle surfaces via coating layer formation was described. The thermodynamics of mixing can provide important information regarding the level of interaction between the components of a system, in other words their miscibility. Phase diagrams were constructed for KETO and ITR/polymer systems. Eutectic compositions and temperatures were calculated for KETO and ITR/polymer systems. It was found that high ITR to polymer ratio ensured the existence of liquid crystalline ITR phases. The findings of this work revealed key findings in relation to NP stabilization and drug polymer interactions. DMPEG was proven to be the most effective stabilizer in terms of achieving colloidal stability for all API NPs. In the case of ITR, quantification of drug polymer miscibility confirmed that low miscibility and solubility between components is a good predictor for effective NP stabilization. In the case of KETO NPs, low miscibility between components was a good predictor for effective NP stabilization. However, some degree of miscibility may be necessary for sufficient physio-sorption of polymer chains onto API surfaces. DLS was utilised to investigate the formation of polymer coating layers onto ITR particle surfaces. DMPEG formed this coating layer more readily than PEG and DMPEG. Layer formation readiness corresponded with effective NP stabilization. Accurate prediction of API polymer interaction may facilitate more efficient stabilizer selection for nano-dispersions. ITR was selected as a model API for the production of solidified nanostructured microparticles (NMPs) via spray drying. Five different water soluble sugars and one sugar alcohol exhibiting a variety of physical properties were explored for inclusion as potential matrix formers, aiding the redispersibility of solidified nano-dispersions. Sugars were added to aqueous nano-dispersions prior to spray drying. ITR NMPs were characterised in terms of their solid state, particle morphology and redispersibility. A subset of these formulations were selected for further tabletting studies. Resulting tablets were examined using a number of standard or modified pharmacopeia tests. The impact of the presence of ITR NMPs upon the processability and tabletability of spray dried sugars was assessed. Trehalose proved to be a better matrix former for ITR NPs boasting superior performance in numerous aspects when compared with mannitol. Namely, compressed ITR NMPs made with trehalose redispersed to smaller average particle sizes upon hydration compared with uncompressed equivalents, confirmed by both NTA and DLS. In addition, trehalose NMPs compressed into tablets exhibited increased tensile strength, compared with mannitol compressed NMPs, with adequate disintegration time maintained. Furthermore, trehalose was capable of solubilising a greater amount of ITR in gastric conditions (0.1M HCl) when compared with mannitol. Solid state effects dominated in determining tablet properties, with amorphous trehalose exhibiting favourable mechanical and disintegrant properties. The matrix former type had a profound impact upon end product performance.