Miniaturization of a Simulated Gastric Fluid Dispersion Experiment On a Microfluidics System - Pharmaceutical Technology

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Miniaturization of a Simulated Gastric Fluid Dispersion Experiment On a Microfluidics System
The miniaturization of preclinical safety assessment studies using a microfluidic chip system and optical microscopy can help reduce compound requirements, time, and costs in formulation development.


Pharmaceutical Technology
Volume 37, Issue 4, pp. 94-100


Figure 3 (a): Schematic representation of the dispersion experiment plan. The yellow channel represents the simulated gastric fluid (SGF); the pink channel the naproxen dissolved in polyethylene glycol 400 (PEG 400); and the grey channel the perfluorodecalin (PFD) carrier fluid. Figure 3(b) is the schematic representation of the second dispersion experiment plan. The SGF droplets were created first and subsequently mixed with the formulation. The yellow channel represents the SGF; the pink channel the naproxen dissolved in PEG 400; and the grey channel the PFD carrier fluid.
Dispersing the naproxen in PEG 400 formulation into SGF directly on the microfluidic chip was attempted next. The design of the experiment is outlined in Figure 3(a) . The naproxen in PEG 400 formulation (see pink channel, Figure 3 [a]), SGF (see yellow channel, Figure 3 [a]), and carrier fluid (PFD, see grey channel, Figure 3 [a] ) were plumbed into three separate lines with the intention of generating droplets of dispersed formulation in SGF separated by the carrier fluid at the junction of the chip. This experiment was somewhat unsuccessful as the high viscosity of the PEG 400 formulation line caused significant backflow issues. The formulation precipitated; however, there was no controlled droplet generation. Looking at the chip under polarized light indicates the naproxen/PEG 400 formulation crashed out of solution generating a crystalline precipitate, which was a promising result; however, more control was desired.


Figure 4. Droplets of the naproxen/polyethylene glycol 400 (PEG 400) formulation dispersed in simulated gastric fluid directly within the microfluidics chip channel, separated with the perfluorodecalin carrier fluid. The image was taken under polarized light.
To achieve more control over the redispersibility experiment, the experimental design was changed. In the new experiment, SGF droplets (see yellow channel, Figure 3 [b]) were first generated in the carrier fluid [see grey channels Figure 3 [b]) and as they exited the chip, the exit line of tubing was replumbed into one of the bottom channels of the microfluidics chip. The second of the lower channels of the chip was plumbed with the naproxen in the PEG 400 formulation (see pink channel, Figure 3[b]). This experiment proved successful as once the formulation was dispersed into the SGF droplets, the new combined droplets continued to travel through the channel. In addition, the timescale was appropriate to observe the precipitation of the naproxen into crystalline material before the newly formed droplets exited the chip (see Figure 4).


Figure 5: Dispersion of the naphthol/Imwitor 742:Tween 80 formulation dispersed in simulated gastric fluid directly within the microfluidic chip channel. The image was taken under polarized light. Inset: nonpolarized light image.
Having demonstrated that it is possible to perform a redispersibility experiment within a microfluidic chip, the final experiment aimed to differentiate between different formulations of a model compound. In this case, formulations of naphthol were prepared at 50 mg/g in PEG 400 and 100 mg/g in Imwitor 742:Tween 80. The difference in concentrations of these two formulations represents the difference in dosing volumes for the vehicles when administered at the same dose. The design of these experiments follows the schematic detailed in Figure 3(b). The naphthol formulation in PEG 400 was dispersed first. As the formulation mixed with the SGF droplets and traveled through the channel, there was no precipitation event (data not shown).

Imwitor 742:Tween 80 is a known self-emulsifying drug-delivery system (SEDDS) (11). SEDDS vehicles are typically comprised of oils and surfactants and solubilize highly lipophilic compounds. Upon reaching the aqueous environment of the stomach, the vehicle creates emulsions, which often boost in vivo exposure. When this formulation of naphthol was mixed with SGF droplets at the T-junction, the emulsifying nature of the vehicle was observed. This emulsion property is particularly evident when viewed under nonpolarized light (see Figure 5 inset). When viewed with the polarizing filter on the microscope, it is clear that the naphthol compound was precipitating out as evidenced by the birefringence observed at the interface of the two solutions. The precipitation, however, was somewhat impeded by the emulsification of the Imwitor 742:Tween 80 vehicle, and no distinct crystal habit was formed (see Figure 5).


Figure 6: Naphthol/polyethylene glycol 400 (PEG 400) formulation before and after dispersion into simulated gastric fluid (SGF) and naphthol/Imwitor 742:Tween 80 [1:1] formulation before and after dispersion into SGF.
Figure 6: Naphthol/polyethylene glycol 400 (PEG 400) formulation before and after dispersion into simulated gastric fluid (SGF) and naphthol/Imwitor 742:Tween 80 [1:1] formulation before and after dispersion into SGF.
Having shown it was possible to disperse a formulation in SGF on a chip, a comparison experiment was conducted examining how the same formulations behave when dispersed in SGF on the benchtop. Standard SGF dispersion experiments were set up where the solution formulations of naphthol in PEG 400 and naphthol in Imwitor 742:Tween 80 [1:1] were dispersed into SGF at a ratio of 1:1. These experiments were run in small scintillation vials equipped with stirbars. Figure 6 shows the formulation vials prior to and after SGF dispersion. The results of the traditional benchtop SGF dispersion experiment parallel what was observed in the microfluidic dispersion experiments. Upon dispersion into SGF, the naphthol in PEG 400 formulation remained a solution, and the naphthol in Imwitor 742:Tween 80 [1:1] formulation became cloudy.


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