Title : Comparison of in vitro drug dissolution profiles: Current state and examination of etravirine tablets
Abstract:
In vitro drug dissolution is a laboratory test of drug tablets to assess product quality. The test measures drug release (i.e. drug dissolution) from tablets. There are numerous scenarios during drug development, as well in post-market life-cycle management, when there are manufacturing changes, such that pre-change and post-change tablets need to be compared, including comparison of in vitro drug dissolution profiles [1]. Given the importance of drug dissolution in product quality, there are numerous regulatory guidance on comparing in vitro drug dissolution profiles, typically employing f2 metric [2]. However, there are considerable differences in the selection of timepoints in comparing dissolution profiles via f2. The objective was to examine the impact of timepoints on computed f2 values.
In vitro dissolution profiles of etravirine were obtained for brand Intelence (Jannsen) and the AB-rated generic etravirine (Amneal) using the method described in the FDA dissolution database [3]. Briefly, Dissolution used USP Apparatus 2 (paddle method) (Hanson SR8 Plus Dissolution Test Station; Chatsworth, CA) at 37 ± 0.5 ?C at 70rpm with three replicates. Medium was two phases. Phase 1 was 500 mL of degassed 0.01 M HCl for 10 min. Phase 2 involved adding 400 mL of 2.25% sodium lauryl sulfate (SLS) in 0.01 M HCl, yielding 900 ml of 1.0 % SLS in 0.01 M HCl. After the start of phase 2, 2 ml of dissolution sample was withdrawn at 5, 10, 15, 20, 30, 45, 60, 90, 120, 240 and 480 min, filtered through a 0.45 mm Millipore filter, and assayed by UPLC analysis at 310 nm. Cumulative percentage drug dissolved from the tablets were calculated. f2 was calculated using several different selections of timepoints.
Graphically, generic reached 80% dissolved by 20min, while brand required 45min. Qualitatively, generic profile was more rapid than brand, although both reflected immediate-release tablets. The generic has been shown to be bioequivalent to brand, and not superior to brand.
f2 results indicate f2 value was very dependent on selection of in vitro dissolution timepoints. Using the BCS M9 guidance timepoints of” 5, 10, and 20 min”, f2 was only 25.3, and substantially lower than the required value of 50 (or more) to be considered similar. The only examined dataset yielding greater than 50 was “60, 90, 120, 240, and 480 min”, resulting in f2=57.4.
In conclusion, f2 value depended on the selection of timepoints, which is problematic since there is a lack of regulatory harmonization in the selection of timepoints. This lack of harmonization reflects the differing points of views from a conservative regulatory perspective and a scientific oral biopharmaceutics perspective.
Audience Take Away Notes:
- Role of in vitro dissolution profiling in drug product quality
- F2 as metric to compare dissolution profiles
- Dependence of f2 values on the selection of dissolution sample timepoints
