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

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2019 Mar 20

PMID 30884755

Citations 7

Authors

Marival Bermejo

Gislaine Kuminek

Jozef Al-Gousous

Alejandro Ruiz-Picazo

Yasuhiro Tsume

Alfredo Garcia-Arieta

Isabel Gonzalez-Alvarez

Bart Hens

Gregory E Amidon

Nair Rodriguez-Hornedo

Gordon L Amidon

Deanna Mudie

Affiliations

Soon will be listed here.

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 C 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.

Citing Articles

In Vivo Predictive Dissolution and Biopharmaceutic-Based In Silico Model to Explain Bioequivalence Results of Valsartan, a Biopharmaceutics Classification System Class IV Drug.

Gonzalez-Alvarez I, Ruiz-Picazo A, Selles-Talavera R, Figueroa-Campos A, Merino V, Bermejo M Pharmaceutics. 2024; 16(3).

PMID: 38543284 PMC: 10974868. DOI: 10.3390/pharmaceutics16030390.

Development of an In Vitro Methodology to Assess the Bioequivalence of Orally Disintegrating Tablets Taken without Water.

Takagi T, Masada T, Minami K, Kataoka M, Yamashita S Pharmaceutics. 2023; 15(9).

PMID: 37765162 PMC: 10535823. DOI: 10.3390/pharmaceutics15092192.

The Bioequivalence Study of Two Dexketoprofen 25 mg Film-Coated Tablet Formulations in Healthy Males Under Fasting Conditions.

Yerlikaya F, Arslan A, Bas H, Saglam O, Aytac S Turk J Pharm Sci. 2023; 20(2):115-120.

PMID: 37161687 PMC: 10176624. DOI: 10.4274/tjps.galenos.2022.95994.

Supersaturation and Precipitation Applicated in Drug Delivery Systems: Development Strategies and Evaluation Approaches.

Gan Y, Baak J, Chen T, Ye H, Liao W, Lv H Molecules. 2023; 28(5).

PMID: 36903470 PMC: 10005129. DOI: 10.3390/molecules28052212.

Characterizing the Physicochemical Properties of Two Weakly Basic Drugs and the Precipitates Obtained from Biorelevant Media.

Zhang M, Wu B, Zhang S, Wang L, Hu Q, Liu D Pharmaceutics. 2022; 14(2).

PMID: 35214062 PMC: 8879660. DOI: 10.3390/pharmaceutics14020330.

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