Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses

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.

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis

“…The gastric fluid buffer capacity is simulated using acetate buffer at 6 mM concentration at altered pH by PPIs listed in Table . The stomach secretion fluid has the same concentration and pH as its initial media. , A description of the GIS in vitro dissolution mass transfer model and quantified hydrodynamic conditions used in the model is provided in appendices 9&10. A hierarchical mass transport model has been used to quantify the dissolution rate of different drugs under different buffer and hydrodynamic conditions of the GIS compartments .…”

An In Vivo Predictive Dissolution Methodology (iPD Methodology) with a BCS Class IIb Drug Can Predict the In Vivo Bioequivalence Results: Etoricoxib Products

“…A potential explanation might be the presence of calcium phosphate in the reference product, which attributes the lower concentration and amount dissolved. We have shown recently that in formulations of dexketoprofen trometamol (salt of a weak acid), excipients that increase pH (calcium phosphate) decreased free acid precipitation and enhanced dissolved levels of drug [ 20 ]. In the case of the weak base the same effect would lead to a slower dissolution rate due to the higher pH around the solid particles.…”

Chitosan-Based Thermo-Responsive Scaffold for Wound Heal-ing Provides Dexketoprofen Trometamol Controlled Release for 24 Hour-Use

“…DKT is a weak acid salt, and the pH value of precipitation (pHp) for this substance in the formulations (i.e., the lowest possible pH where the API is still ionized) is 6.12. As a result, a lower pH can cause the precipitation of the API as DK, the lipophilic-weak acid [13].…”

“…Dexketoprofen (DK) -a non-selective COX inhibitor-is the (S)-(+)-enantiomer of ketoprofen. It is used for the rapid management of mild to moderate pain with a maximum daily dose of 75 mg, administered as the tromethamine salt derivate, Dexketoprofen trometamol (DKT), that is a class 1 drug (i.e., high solubility and high permeability) according to the Biopharmaceutical Classification System (BCS) [13]. Different approaches to the delivery of DKT have been made, especially for the development of oral formulations [14,15].…”