Manufacturing Amorphous Solid Dispersions With Improved Solid-State Stability

Although amorphous solid dispersion(ASD) is a promising strategy for enhancing drug solubility, it has not been recognized to its full potential due to a lack of understanding as to how solid state stability is affected by manufacturing conditions such as method of preparation, formulation parameters (choice of excipients, drug-polymer ratio), processing conditions, and in part due to a lack of characterization techniques available to study drug-polymer miscibility and intermolecular interactions in the solid state. Therefore, to purpose of this research was to provide for a strong basis and insight to further develop robust and cheap ASD formulations. Chapter 1 discusses the relevant background, and specifies the objectives of this work in further detail. Chapter 2 is a detailed literature review providing an overview of the manufacturing techniques for preparing ASDs. As physical stability is a critical quality attribute for ASD, the impact of formulation, equipment, and process variables, together with the downstream processing on physical stability of ASDs have been discussed.

Chapter 3 presents the development of an advanced surface characterization platform consisting of two complementary techniques: X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS). Such a platform enables qualitative and quantitative measurements of surface composition for the fine spray dried ASD particles with ultra-surface-sensitivity (less than 10 nm from the surface) and superior spatial resolution (approximately 250 nm for ToF-SIMS). In Chapter 4, spray-dried amorphous solid dispersions (ASD) of naproxen produced using a three fluid nozzle (3FN) were compared with those prepared using a two fluid nozzle (2FN) for physical stability. Upon storage of the formulated ASDs at different humidities, naproxen crystallized more quickly from the 3FN ASDs as compared with the 2FN ASDs. This relatively higher crystallization tendency of 3FN ASDs was attributed to the inhomogeneity of drug and polymer as identified by the solid-state Nuclear Magnetic Resonance findings, specifically due to poor mixing of water- and acetone-based solutions at the 3FN nozzle. This study provides insights into the effects of solvent and nozzle choices on the physical stability of spray-dried ASDs.

Although processes like spray drying and melt extrusion enjoy widespread acceptance as commercial ASD manufacturing methods, their high capital cost of equipment discourages their application in developing countries. Chapter 5 and 6 aimed to develop amorphous solid dispersion (ASD) with a cost-effective manufacturing approach. Chapter 5 reports the development of lumefantrine ASDs by spray anti-solvent precipitation. The choice of polymer, and the drug-polymer ratio played a crucial role in the solubility enhancement of lumefantrine. Chapters 6 discusses the formulation ivermectin ASDs by a combination approach of anti-solvent precipitation followed by spray drying. ASDs of prepared by spray-drying alone exhibited a stability and dissolution profile similar to those prepared using the combination of precipitation and spray drying with the same drug load. This study indicates the developed manufacturing method of anti-solvent precipitation followed spray drying is a promising approach for producing ivermectin ASDs.