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. This study was designed with the intent of comparing these techniques in a critical manner. NPs were formed using three Biopharmaceutics Classification System class II compounds: itraconazole, ketoconazole and posaconazole, using an anti-solvent addition, bottom up method. The impact of polyethylene glycol, polyethylene glycol methyl ether and polyethylene glycol dimethyl ether with a molecular weight 2000 Da, 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 posaconazole 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 nanoparticle.
In this work we report the effect of stabilizer choice and concentration on nanoparticle (NP) stability over time. Three different BCS class II active pharmaceutical ingredient (APIs): itraconazole (ITR), ketoconazole (KETO) and posaconazole (POS) were chosen due to their poor aqueous solubility and closely related chemical structures. Polyethylene glycol, polyethylene glycol methyl ether and polyethylene glycol dimethyl ether (DMPEG) with a molecular weight of 2000 Da were included as stabilisers. 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. Kinetic modelling indicates nanoparticle growth is driven by Ostwald ripening (OR). The presence of DMPEG causes OR growth to become an interface controlled process following a parabola trend. DMPEG encourages OR for POS NPs whilst driving the crystallisation process. The rate of OR appears to be inherent of the crystallisation pathway by which these APIs proceed. Crystallisation mechanisms are API, stabilizer type and concentration dependent. DLS is suitable as an initial systematic screening method for stabilizer selection, aiding the pharmaceutical scientist in the optimisation of nano-formulations.
The addition of matrix formers within a formulation provides a means for enhancing the redispersibility of nanoparticles (NPs) enabling them to retain their advantageous properties imparted onto them by their sub-micron size. In this work, NPs were isolated in the solid state via spray drying with a range of sugars. The processed powders were characterized, establishing that itraconazole (ITR) nanostructured microparticles (NMPs) spray dried in the presence of mannitol and trehalose had favorable redispersibility confirmed by dynamic light scattering and nanoparticle tracking analysis. Solid-state analysis confirmed the crystalline nature of NMPs based on mannitol and the amorphous character of trehalose-based NMPs. The NMPs powders were compacted at a range of pressures, producing tablets with high tensile strength without compromising their disintegration time. A greater amount of ITR was solubilized from trehalose NMPs compared to the mannitol-based compacts in 0.1 M HCl, showing a promise for enhanced in vivo activity. Overall, as trehalose exhibited superior carrier properties for ITR NMPs, this type of excipient included in the formulation warrants careful consideration. The structured approach to matrix former selection and tabletting studies can reduce the amount of material and time required for testing in the initial stages of product development.
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