Investigating Permeation Behavior of Flufenamic Acid Cocrystals Using a Dissolution and Permeation System

Abstract

The dissolution and permeation of the cocrystals, flufenamic acid-nicotinamide (FFA-NIC) and flufenamic acid-theophylline (FFA-TP), have been investigated in the presence of two polymers, polyvinylpyrrolidone (PVP) and copolymer of vinylpyrrolidone/vinyl acetate (PVP-VA), using a dissolution/permeation (D/P) system. It showed that the types and concentrations of the polymers and their interactions with the coformers had significant effects on the dissolution and permeation of the FFA cocrystals. The role of PVP as a stabilizing agent was not altered in spite of its interaction with the coformer of NIC or TP, which was supported by the proportional flux rate of FFA to the dissolution performance parameter (DPP). With an appropriate PVP concentration, the maximal flux rate of FFA could be obtained for a given FFA cocrystal. The situation was complicated in the presence of PVP-VA. The role of PVP-VA could change because of its association with the coformers, i.e., from a stabilizing agent to a solubilization agent. In addition, PVP-VA reduced the flux rate of FFA, in contrast to its DPP for FFA cocrystals. Finally,H NMR provided evidence regarding the molecular interactions between FFA, coformers, and polymers at the atomic level and gave insight into the mechanism underlying the supersaturated solution and subsequent permeation behavior of the cocrystals.

Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient

“…A supersaturated solution concentration of the parent drug can be generated due to rapid dissolution of cocrystals, which is a key requirement for improved drug oral absorption . It is thus critical to include a polymeric excipient in the formulation as an inhibitor to prevent the parent drug crystallization and to maintain drug in solution in aqueous media for a sufficient length of time to allow absorption. − Selection of a polymeric excipient in a cocrystal formulation can be problematic because the interplay of the polymer with both the parent drug and coformer in solution could lead to erratic drug release performance in vitro or in vivo. , Therefore, a thorough understanding of the dissolution mechanisms of cocrystals and their possible interaction with the excipients and dissolution environments is required to guide preclinical formulation development. , …”

Combining Co-Amorphous-Based Spray Drying with Inert Carriers to Achieve Improved Bioavailability and Excellent Downstream Manufacturability

“…A dissolution/permeation (D/P) system was used to simultaneously investigate the dissolution and permeation profiles of drugs under the non-sink condition [20,21]. This was utilized for evaluating the ability to prolong the supersaturation of APIs of spray-dried preparations and the artificial membrane permeability of APIs at physiological pH to understand the oral absorption of both drugs.…”

“…The dissolution performance parameter (DPP) [21] and the flux rate [20] were used to evaluate the dissolubility and permeability of the solid samples.…”

Preparation, characterization, and pharmacokinetics of rivaroxaban cocrystals with enhanced in vitro and in vivo properties in beagle dogs

“…In recent decades, great efforts have been made to improve solubility, permeability, or bioavailability of poorly water-soluble drugs by inserting a more soluble coformer in the crystal lattice leading to a reduced solvation barrier ( Cysewski, 2018 ; Dalpiaz et al, 2018 ; Liu et al, 2016 ; Wen et al, 2005 ). Cocrystals can also enhance membrane permeation and diffusion due to the induced supersaturated drug concentration ( Ferretti et al, 2015 ; Guo et al, 2018 ; Liu et al, 2020b ).…”