Abstract
The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt—Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence (non-BE) tablet group achieved higher plasma Cmax and area under the curve (AUC) than the reference and BE tablets groups, with only one difference in tablet composition, which was the presence of calcium monohydrogen phosphate, an alkalinizing excipient, in the tablet core of the non-BE formulation. Concentration profiles determined using a gastrointestinal simulator (GIS) apparatus designed with 0.01 N hydrochloric acid and 34 mM sodium chloride as the gastric medium and fasted state simulated intestinal fluids (FaSSIF-v1) as the intestinal medium showed a faster rate and a higher extent of dissolution of the non-BE product compared to the BE and reference products. These in vitro profiles mirrored the fraction doses absorbed in vivo obtained from deconvoluted plasma concentration–time profiles. However, when sodium chloride was not included in the gastric medium and phosphate buffer without bile salts and phospholipids were used as the intestinal medium, the three products exhibited nearly identical concentration profiles. Microscopic examination of DKT salt dissolution in the gastric medium containing sodium chloride identified that when calcium phosphate was present, the DKT dissolved without conversion to the less soluble free acid, which was consistent with the higher drug exposure of the non-BE formulation. In the absence of calcium phosphate, however, dexketoprofen trometamol salt dissolution began with a nano-phase formation that grew to a liquid–liquid phase separation (LLPS) and formed the less soluble free acid crystals. This phenomenon was dependent on the salt/excipient concentrations and the presence of free acid crystals in the salt phase. This work demonstrated the importance of excipients and purity of salt phase on the evolution and rate of salt disproportionation pathways. Moreover, the presented data clearly showed the usefulness of the GIS apparatus as a discriminating tool that could highlight the differences in formulation behavior when utilizing physiologically-relevant media and experimental conditions in combination with microscopy imaging.
Highlights
The development of generic oral drug products containing dexketoprofen trometamol (DKT, weak acid salt, Biopharmaceutics Classification System (BCS) class 1 drug) is challenging as the reference product does not dissolve rapidly
In Spain, three out of four formulations of DKT tablets failed the first in vivo bioequivalence (BE) study [3]. These products were previously tested with the European Medicines Agency (EMA) dissolution method requested for biowaiver applications, i.e., performing dissolution tests in USP-2 apparatus at 50 rpm with different buffers at pH 1.2, 4.5, and 6.8
Two concentration levels of both DKT and excipients were studied by varying the amount of DKT and excipients added to 96-well plates followed by the addition of 300 μL of hydrochloric acid (pH 2 (0.01 M) and 34.2 mM NaCl) with pre-dissolved tablet excipients
Summary
The development of generic oral drug products containing dexketoprofen trometamol (DKT, weak acid salt, Biopharmaceutics Classification System (BCS) class 1 drug) is challenging as the reference product does not dissolve rapidly. In Spain, three out of four formulations of DKT tablets failed the first in vivo bioequivalence (BE) study [3]. These products were previously tested with the European Medicines Agency (EMA) dissolution method requested for biowaiver applications, i.e., performing dissolution tests in USP-2 apparatus at 50 rpm with different buffers at pH 1.2, 4.5, and 6.8. Dissolution profiles of one DKT product using USP apparatus 2 (pH 1.2, 4.5, and 6.8) exhibited profiles (f 2 < 50) that were not similar to in vivo BE Another product exhibited in vitro BE (f 2 > 50) but failed the in vivo BE study. The USP apparatus 2 did not reflect the in vivo BE outcome
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
