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


The following materials were used in the study: naproxen (Chemical Abstracts Service [CAS] Number 22204-53-1, Sigma-Aldrich); naphthol (CAS Number 90-15-3, Sigma-Aldrich); perfluorodecalin (PFD) (CAS Number 306-94-5, Acros Organics), polyethylene glycol 400 (PEG 400, CAS Number 25322-68-3, Sigma Aldrich; Imwitor 742 (Sasol), and polysorbate 80 (CAS Number 9005-65-6, Tween 80, Fisher Scientific.

Formulations were prepared at 50 mg/g concentration representing a 100 mg/kg dose in vivo when PEG 400 is dosed at 2 mL/kg. Model compounds naproxen and naphthol were fully solubilized at this concentration. In addition, naphthol was prepared at 100 mg/g in 1:1 Imwitor 742:Tween 80. The compound also was fully solubilized. SGF was prepared by dissolving 2.0 g of sodium chloride (NaCl) in 1 L of deionized water and adjusting the pH to 1.2 with 1 N HCl (hydrochloride acid).

The microfluidics system was from Dolomite Microfluidics, and the experiments were run on a standard quartz T-junction chip with a channel size of 190 m. The reagents were fed into the chip using three Dolomite Mitos Pressure Pumps (P-Pumps) with the pressure attenuated based on the viscosity of the liquids. The experiments were run at room temperature. After the experiments were completed, the chips were disassembled and transferred to either a Zeiss Axiovert 200M inverted microscope or a Nikon Eclipse E800 microscope, both equipped with a polarizing light filter to assess crystallinity.

Results and discussion

Figure 1: Quartz microfluidic channel chip used in experiments as compared to the size relative to a penny and the schematic representation of the chip (top) and the naproxen formulation in polyethylene glycol 400 (PEG 400) dispersed as a plug in the carrier fluid perfluorodecalin (PFD) (bottom). The plug is optically distinguishable from the carrier fluid and also traveled freely through the channel.
The microfluidic system used for this study was the Dolomite pressure-based droplet microfluidics system. The experiment required three Mitos-P pumps with one equipped with a three-way outlet head. A standard quartz channel chip was used, which was optically transparent and stable to organic reagents. Figure 1 shows an image of the chip relative in size to a penny and also the schematic representation that is used throughout this article. In the T-junction schematic, the phase coming through Channel B would be considered the “dispersed” phase that would be dispersed within the “continuous” phase flowing though Channels A and C.

The lines are supplied by the Dolomite P pumps, with the pressures adapted to the individual viscosity of each liquid and until suitable droplet size is achieved (droplets of B within the carrier fluid channeled through Channels A and C).

The goal of these experiments was to see whether a typical redispersibility experiment could be performed on a droplet-generating microfluidics system. The redispersibility experiment involves preparing a formulation, either solution- or suspension-based, of a new chemical entity in a dosing vehicle and then dispersing the formulation into a biorelevant medium. Potential outcomes include the compound crashing out as either crystalline or amorphous physical phase or the compound remaining completely solubilized. If the starting formulation is a solution, when the compound of interest precipitates from the formulation vehicle, it is considered a less favorable formulation as this will render the active compound less absorbable in the intestinal barrier.

The initial experiment performed was to generate a plug of a solution formulation of naproxen dissolved in PEG 400 within the carrier fluid, PFD, to verify that the viscous PEG 400 would travel through the channel of the chip, which proved successful (see Figure ). PFD was chosen because as a fluorocarbon, it is immiscible with PEG 400 and the aqueous-based SGF. In this experiment, the carrier fluid was plumbed through Channels A and C as depicted in Figure 1, and the naproxen/PEG 400 formulation was brought in through Channel B. The naproxen/PEG 400 formulation was successfully “plugged” in the PFD carrier fluid and was visually distinct and traveled easily through the microfluidic channel.

Figure 2: Benchtop-dispersed droplets of a naproxen/ polyethylene glycol 400 (PEG 400) formulation in simulated gastric fluid within the microfluidics chip channel separated with the perfluorodecalin carrier fluid. The image was taken under polarized light.
Next, the same naproxen in the PEG 400 formulation was dispersed into SGF on the benchtop, and the resulting suspension was plumbed through the chip. The experimental design was the same in that Channels A and C were the PFD carrier fluid and Channel B was the suspension of the naproxen formulation dispersed (on the benchtop) in SGF. This experiment verified that plugs of a formulation suspension could travel through the channel of the chip. For visualization, the chip was removed from the microfluidics chip-holder system and examined with polarized light microscopy. The characteristic birefringence was observed through the quartz chip, suggesting that the naproxen precipitates from the PEG 400 as crystalline material (see Figure 2).


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