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

Conclusion

These experiments demonstrate the proof of concept that a dispersion experiment can be performed within a T-junction microfluidics chip system. When individual droplets of SGF were mixed with formulations at the T-junction, the model compounds either stayed in solution or precipitated out. When the compounds did precipitate out, information about the physical form of the precipitated chemical entity was obtained as the microfluidic chip is visualized under polarized light microscopy.

As there are significant benefits, scaling down redispersibility experiments also was explored by other groups. Dai and Mansky (12, 13) describe a method using a 96-well plate that uses a small amount of compound to screen the solubilizing effect of several excipients once dispersed into simulated intestinal fluid [SIF]. The method is further validated by comparing the results of the miniaturized experiments to traditional formulation dissolution testing and actual in vivo studies (14). In addition, Gopinathan et al. (15) developed a 96-well plate based high-throughput formulation screening strategy. The company TransForm (16, 17) has developed similar high-throughput formulations screens, even extending to a 384-well plate. For these examples, the reagents are mixed by vortexing or sonicating the plate, or in some cases, heating to solubilize the initial compound. These examples illustrate the direction the pharmaceutical industry is headed with respect to formulation screening in the discovery space: using small amounts of compound to evaluate many different formulations. The experiments detailed in this article are complementary as they use microfluidic technology, specifically T-junction droplet generation. Although not as developed as the aforementioned examples, this method offers the potential benefit of in situ mixing that droplet microfluidics offers (18, 19). This feature would be beneficial when highly viscous formulations are evaluated and may be a better representation of how formulations are dynamically mixed in the gastrointestinal tract. Further, microfluidic technology has the potential to consume even less compound than what would be used in a 384-well plate experiment.

Future experiments under consideration by the authors include a two-step SGF and fasted state SIF redispersibility study that would more closely mimic the transport of a compound from the acidic environment of the stomach to the more neutral pH (i.e., pH 6.5) of the small intestine. In addition, the system can be temperature-controlled, and the effect of temperature on these types of experiments may be explored.

In summary, scaling down redispersibility experiments to the microfluidic scale has the potential to have significant impact on how formulations are screened in the pharmacuetical industry. Performing redispersibility experiments on a much smaller scale allows more formulations to be screened in vitro using less material. When combined with more powerful detection techniques, the experiment also can provide more understanding of the behavior of the physical phase in the gastrointestinal environment. This information can help formulation development scientists identify and understand the most effective formulations for future in vivo experiments more efficiently.


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