(M1330-08-50) The Effect of Sampling Cannula on In Vitro Dissolution Testing with USP Paddle Method

Purpose: In vitro dissolution tests are widely used as quality control tools for drug products in product development and under regulatory review. As a standard method, the repeatability and reproducibility of dissolution testing were a concern after the methods became official in the US Pharmacopeia (USP) in the early 1960s. Understanding potential sources of variation is critical and a key to assuring reliable results are obtained when using a standardized system for in vitro dissolution testing. Sampling cannulas are commonly used to withdraw sample aliquots from dissolution medium by either an automated or manual sampling procedure and are especially useful when the method requires sample aliquots be collected at different time points. Sampling cannulas are potentially one of the essential testing factors that can contribute to variations in dissolution testing, especially when using a sampling cannula with a tip filter commonly having an outer diameter (OD) about 9 mm. However, there are still no clear requirements on the size or setting (intermittent or stationary) of sampling cannulas for dissolution testing. Thus, the objective of this study is to evaluate whether different size and sampling cannula settings yield different dissolution results using the USP 2 apparatus.

Methods: Dissolution testing was performed in 500 mL degassed deionized (DI) water at 37°C using a USP paddle method (Hanson Vision 8 apparatus) with 50 rpm paddle rotation speed. Prednisone 10 mg disintegrating tablet (NCDA#2) was used in this study to examine sampling cannula effects on the dissolution results. Sampling cannulas within the range of 1.6 – 9.0 mm OD were used in dissolution testing with either intermittent or stationary settings to collect 5mL sample aliquots at 5, 15, 20, 30, 45 and 60 minute time points. All aliquots were drawn from the dissolution medium and passed through a 10 µm filter (either in-line filter or tip filter) into labeled sample collectors. Sample aliquots were analyzed with an UV-Vis spectrophotometer (Agilent 8454) measuring the absorbance at 242 nm with a single 400 nm wavelength background correction. The dissolution results at each time point were statistically analyzed for effects of both size (OD) of sampling cannula and setting of sampling procedure on drug release from NCDA#2 tablet.

Results: Considering the size of current commercially available filters used in dissolution testing, sampling systems requiring a filter at the end of the cannula can increase the size of the cannula up to 9 mm OD. The results showed statistically significant (p < 0.05) increases in dissolution results when the sampling cannula OD was larger than 3.6 mm. For the 30 minute time point, the drug release increased over 25% when comparing the results of sampling cannulas with OD of 9.0 mm to 1.6 mm regardless if the sampling cannula was in the intermittent or stationary setting. For commonly used commercially available 3.6 mm (OD) sampling cannula, the dissolution results at 30 minute showed larger deviations in the stationary setting (6.4%) than in the intermittent setting (2.2%) when comparing the dissolution results for the 1.6 mm OD sampling cannula.

Conclusion: The results indicate that sampling cannula can cause significant variations in dissolution results. Sampling cannula size should be documented in the standard operating procedure (SOP) for dissolution testing during method development. Sampling cannula with OD less than 3.6 mm may be required for in vitro dissolution studies to reduce variations. Sampling systems requiring a filter at the end of each sampling cannula, in either the intermittent or stationary setting, should be avoided.

Acknowledgements: Authors appreciate Mr. Kaisen Yao, who participated this study as a summer intern, and conducted in vitro dissolution testing for the project.

Funding: Mr. Kaisen Yao was supported in part by an appointment to the Research Participation Program at the CDER, U.S. Food and Drug Administration, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and FDA. Disclaimers: This poster reflects the views of the authors and should not be construed to represent FDA’s views or policies.

Impact of sampling cannula on dissolution testing with USP paddle method