Controlling the solid-state and particle properties of a fixed-dose combination co-amorphous system by spray drying†

Abstract

Controlling the solid-state stability of co-amorphous drug delivery systems has been an ongoing challenge in the pharmaceutical field to date. The main route to stabilise co-amorphous systems is to increase excipient load either in the co-amorphous formulation or via an additional excipient, creating a ternary amorphous system. Increasing excipient load in a formulation can have disadvantages such as producing large oral dosage forms. In this work, the impact of spray drying process parameters on the formation and short-term stability of a drug–drug co-amorphous mixture in the absence of any excipients is investigated. A 9-point design of experiments (DoE) was conducted to assess the impact of atomising gas flowrate and feed flowrate on the co-amorphous formation and stability. It was found that when the outlet temperature was fixed at 50 °C, the atomising gas flowrate had a more significant effect on the physical stability of the co-amorphous mixture than the feed flowrate. Monitoring the stability of formulations at accelerated stability conditions (40 °C per 75% relative humidity) showed that the co-amorphous systems produced at higher atomising gas flowrates, with smaller droplet sizes and subsequent particle sizes, exhibited a higher stability than those produced at lower atomising gas flowrates. Co-amorphous systems produced at the higher atomising gas flowrates remained stable for the 3-month stability testing period demonstrating that the co-amorphous physical stability can be controlled by optimising the spray drying process. The results presented in this study have significant implications for producing co-amorphous drug delivery systems with a high physical stability without the addition of excipients by spray drying.