Comparison of WHO and US FDA biowaiver dissolution test conditions using bioequivalent doxycycline hyclate drug products.

Objectives: The dissolution characteristics of immediate-release doxycycline hyclate products with certified in-vivo bioequivalence to the innovator product were tested with a view to possible application of biowaiver-based approval.

Methods: Five products were tested using US Pharmacopeia Apparatus 2: Antodox 100 mg hard gelatin capsules, Doxycyclin AL 100 T tablets, Doxycyclin-ratiopharm 100 soft gelatin capsules, Doxycyclin STADA 100 mg tablets and Doxy-Wolff 100 mg tablets. Three compendial buffers were used as dissolution media: simulated gastric fluid without pepsin, pH 1.2, acetate buffer, pH 4.5, and simulated intestinal fluid without pancreatin, pH 6.8. Results were obtained at two paddle speeds recommended for biowaiver applications: 75 rpm (World Health Organization; WHO) and 50 rpm (US Food and Drug Administration; US FDA).

Key Findings: The results for the tablets and hard gelatin capsules indicate that a paddle speed of 75 rpm is more representative than 50 rpm, since 75 rpm generates dissolution profiles corresponding more closely to the in-vivo profiles than those at 50 rpm. For evaluating soft gelatin capsule formulations with lipid fill, both US FDA and WHO methods were found to be over-discriminating.

Conclusions: Bioequivalence of immediate-release doxycycline hyclate tablets and hard gelatin capsules, but not soft gelatin capsules, can be evaluated in vitro using the biowaiver dissolution test conditions specified by the WHO.