(T1430-03-20) The Impact of Particle Size of the Drug Substance on Dissolution of Finished Product for the Treatment of Cushing’s Disease in Dogs

Purpose: For drug product development, it is essential to investigate various particle size of drug substance to determine the best possible formulation for the drug product. The purpose of this study is to determine an appropriate particle size of drug substance and formulation components for the drug product for the treatment of Cushing’s disease in dogs.

Methods: Generally, small particle size of drug substance in the micrometer range increases the dissolution and positively impact the in vivo performance. However, a larger drug substance particle size improves manufacturability because it has better flow. In order to understand the appropriate drug substance particle size distribution range for development study, five prototype formulations were evaluated from two drug substance manufacturers. The drug products were manufactured by direct blending followed by encapsulation. The formulations were characterized for assay, in vitro dissolution study and related substance. Dissolution of the capsules were performed using 900 mL of pH 8.0 phosphate buffer at 37.0ºC ± 0.5ºC, Apparatus I (Baskets), at 100 RPM.

Results: The dissolution test was performed on the two prototypes using API from manufacturer 1 and three prototypes using API form manufacturer 2. The results are presented in the Figure 1 and Figure 2, respectively. The data indicated that manufacturer 2’s API exhibited faster dissolution in general. A dissolution rate of not less than (NLT) 80% in 30 minutes in pH 8.0 buffer was set as the target for pharmaceutical development studies. Since Batch 3 (D90=16 μm) showed 89% dissolution in 30 minutes, the API from manufacturer 2 with particle size D90 more than 15 μm was selected for the capsule pharmaceutical development.

Conclusion: By investigating various drug substance venders and the particle size range, the appropriate particle size has been determined. With appropriate formulation components, the drug product has been successfully manufactured for in vivo testing.

Figure 1. In-vitro dissolution studies of the drug product capsules with API from manufacturer 1 using USP apparatus I in 900 mL of pH 8.0 buffer at 100 rpm

Figure 2. In-vitro dissolution studies of the drug product capsules with API from manufacturer 2 using USP apparatus I in 900 mL of pH 8.0 buffer at 100 rpm