(M1330-11-61) Performance Verification Variations Within Mechanical Calibration Allowance of Paddle Apparatus with Standard and Apex Vessels

Purpose: Dissolution measures the extend and rate of a drug API appearance in the dissolution media from the formulation, and is important in formulation development, quality assurance, bioequivalence assessment, in vitro in vivo correlation, and post approval changes. The dissolution paddle tester (USP Apparatus 2) has been a widely used method across industry to evaluate the rate of drug dissolution from the formulation. The United States Pharmacopeia (USP) has issued standards and mechanical parameters for tester calibration to promote the use and consistency of results across research groups. The USP issued a new Dissolution Performance Verification Standard (DPVS) – Prednisone Reference Standard in 2023, along with a new set of Performance Verification Test (PVT) criteria to be performed in addition to mechanical calibration for instrument qualification. Apex vessels are dissolution vessels with a convex bottom to reduce coning. In this study, we investigated the effects of changing mechanical calibration parameters within the mechanical calibration allowance and their impacts on the rate of dissolution for new DPVS – Prednisone tablets in deaerated water using both standard and apex vessels as well as whether the apparatus configuration meets the PVT acceptance criteria.

Methods: Dissolution Performance Verification Standard - Prednisone (DPVS-Prednisone) RS tablets (Lot F161Y0) and prednisone USP reference standard (Lot R083A0) were purchased from USP. Dissolution was performed according to the DPVS-Prednisone RS tablet instructions [1] on a Distek 2100A Dissolution System using the paddle apparatus with 6 dissolution vessels. Deaerated MilliQ water was used as the dissolution medium. The agitation rate is specified in Table 1 from 0 to 60 min followed by an infinity spin at 150 rpm from 60 to 75 min. At 10, 20, 30, 45, 60 and 75 min, automatic sampling and quantification were performed on an Agilent 8453 UV-visible spectroscopy system at 242 nm. Distek 10 micro filter tips (Part # 5720-0203) were used with on-line cannulas. In the off-set groups, vessel verticality, paddle depth and rotational speed were varied with the extremes of 1 degree, +/- 2 mm, and +/-1 degree, respectively. The geometric mean (GM) of the %dissolved and correlation of variation (%CV) were calculated for the First and Second Stage according to [1]. The dissolution rate was calculated by (%dissolved-t2 – %dissolved-t1)/(t2 – t1) and compared between the apex and the standard vessel groups. Six units were tested in each stage.

Results: In the no-offset groups, the standard vessel group passed the PVT in both stages with the GM and %CV of 53.4, 2.8% and 53.3, 3.1% of the First and Second Stage, respectively, at 30 min. The apex group failed the PVT in both stages with the GM and %CV of 102.8, 1.0% and 102.0, 1.7% where GM exceeded the acceptance criteria of 48-57 and 46-59 of the First and Second Stage, respectively. In the offset groups, all standard vessel groups passed the Second Stage PVT but three groups failed the First Stage (Table 1). All apex groups failed PVT with GM exceeding the acceptance. The biggest dissolution rate difference was observed at the first time point at 10 min, followed by 20 min, which corresponded to the time when the USP DPVS – Prednisone RS tablets disintegrated, and the disintegrated mass either covered the convex of the apex vessel or formed a cone in the standard vessel. In the apex vessel, the dissolution rate was close to zero after 30 min due to complete dissolution of the tablet, which indicated the dissolution had already been complete prior to 30 min. In the standard vessel, the dissolution rate was below 0.8%/min due to the cone formation which trapped prednisone between 30 to 60 min. The increase after 60 min was because of the increased agitation rate that freed prednisone from the cone.

Conclusion: The dissolution in an apex vessel is faster and more complete than in a standard vessel in the case of immediate release disintegrating tablets containing drug with low solubility and prone to coning, such as USP Dissolution Performance Verification Standard - Prednisone (DPVS-Prednisone) RS tablets. Between an apex and a standard vessel, the largest difference of prednisone dissolution rate was observed at 10 min regardless of the mechanical offset. All apex vessel groups failed the performance verification test (PVT) regardless of the mechanical offset. The results indicate new RS tablets or PVT should be considered for apex vessels, or other options would need to be explored to complete the performance qualification of a paddle apparatus using apex vessels. For all apex vessel groups, the geometric mean failed by being higher than the acceptance range. In contrast, all standard vessel groups passed PVT regardless of the mechanical offset.

References: 1. https://static.usp.org/pdf/EN/referenceStandards/certificates/1222818-F161Y0.pdf

Acknowledgements: This project was supported in part by an appointment of Ethan J Pozy to the Research Participation Program at the 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 the U.S. Food and Drug Administration. This presentation reflects the views of the authors and should not be construed to represent FDA’s views or policies.


Table 1. Mechanical parameter [set value (offset)] and GM and %CV values of the three groups that failed in the First Stage and their results from the Second Stage.