Application of in-line viscometer for in-process monitoring of microcrystalline cellulose-carboxymethylcellulose hydrogel formation during batch manufacturing.

Physical stability and consistent dose delivery of pharmaceutical suspension formulations comprised of microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (NaCMC) hydrogels is dependent on their rheological properties. To obtain the desired rheological characteristics, good control of the hydrogel dispersion in water is required. The goal of this study was to evaluate whether the XL7-100 Process Viscometer could be employed as a process analytical technology (PAT) tool to monitor the dispersion process in real time during batch manufacturing. Using this instrument, viscosity profiles were measured during the hydrogel processing for a range of operating conditions. It was confirmed that viscosity obtained by the XL7-100 Process Viscometer in the off-line mode, could be linearly correlated to that of the conventional Brookfield viscometer. In addition, the XL7-100 Process Viscometer was able to detect variations in the hydrogel concentrations as well as process conditions in real time. Under fixed operating conditions, the dynamic viscosity profile showed low variability and good inter-batch reproducibility for a properly dispersed hydrogel. For a well-validated mixing process, an off-trend in-line viscosity reading may be indicative of batch failure or poor dispersion homogeneity. Therefore, the in-line viscometer can be used in manufacturing to monitor the batch to batch consistency. However, it is not proven to be able to characterize the real-time structure formation of the hydrogel. It is recommended that the in-line viscometer be used as a complimentary tool along with the off-line rheometer for both efficient and effective in-process quality control of the MCC & NaCMC hydrogel dispersion.

Particle size coarsening induced by valve silicone in a metered dose inhaler.

The objective of this study was to evaluate the effect of valve silicone on the delivered particle size distribution of a suspension metered dose inhaler (MDI). Valves were manufactured with distinct levels of silicone, which could be differentiated with Fourier transform infrared spectroscopy (FT-IR). The amount of silicone in the valve was proportional to the amount of silicone that entered the formulation and the subsequent decrease in fine particle fraction (FPF) of the active pharmaceutical ingredient (API) measured by Andersen cascade impaction. The effect of silicone content was not linear as even small amounts of silicone made a significant contribution to particle size coarsening. This coarsening was also a function of storage time and temperature. Accelerated stability conditions greatly increased coarsening kinetics as 1 month at 40 degrees C and 75% RH induced significantly more coarsening than 12 months at room temperature. Field emission scanning electron micrograph images suggest that the primary mechanism of particle size change may be aggregation as particle clusters were seen. This study indicates that silicone can be a critical process parameter for particle size distribution of a suspension MDI product. Thus, the amount of silicone in the valves needs to be minimized and controlled.

Influence of the valve lubricant on the aerodynamic particle size of a metered dose inhaler.

Presented in this work are the results of a study designed to investigate the impact of valve lubricant (i.e., silicone oil) on the aerodynamic particle size distribution (PSD) of a steroid suspension metered dose inhaler (MDI) containing propellant HFA-227. The objective of this study was to explore whether the valve lubricant, which is often used in MDI products to prevent valve sticking, can enter an MDI product and potentially impact the aerosol spray dynamics. The results of this work have shown that samples containing valves with high silicone levels produced a larger aerodynamic particle size (by cascade impaction) than samples with low-silicone or silicone-free valves. It is postulated that the presence of silicone in the product may increase the propensity for drug aggregation, thereby leading to an increase in the aerodynamic particle size of the emitted aerosol. These findings stress the importance of evaluating the effects of valve lubricant on the aerodynamic PSD in the early formulation development stage of an MDI.