Researchers at the University of Illinois at Chicago have developed a new continuous-flow microfluidic device that could help scientists and pharmaceutical companies more effectively study drug compounds and their crystal shapes and structures, which are elements keys to drug stability.
The device consists of a series of wells in which a drug solution – composed of an active pharmaceutical ingredient, or API, dissolved in a solvent, such as water – can be mixed with an anti-solvent in a highly controlled manner. . When mixed, the two solutions allow API crystals to form a nucleus and grow. With the device, the rates and ratios at which the drug solution is mixed with the anti-solvent can be changed in parallel by scientists, creating multiple conditions for crystal growth. As crystals grow under different conditions, data on their growth rates, shapes and structures is gathered and imported into a data network.
With the data, scientists can more quickly identify the best conditions for making the most stable crystal form with desirable crystal morphology – a crystal with a plate shape instead of a crystal with a rod shape – from an API. and intensify the crystallization of stable forms.
UIC researchers led by Meenesh Singh, in collaboration with the Enabling Technologies Consortium, validated the device using L-histidine, the active ingredient in drugs with the potential to treat conditions such as rheumatoid arthritis, allergic diseases and ulcers. The results are reported in Lab-on-a-chip, a journal of the Royal Society of Chemistry.
“The pharmaceutical industry needs a robust screening system capable of accurately determining API polymorphs and crystallization kinetics in a shorter time frame. But most parallel and combinatorial screening systems cannot actively control synthesis conditions, leading to inaccurate results, ”said Singh, UIC assistant professor of chemical engineering at the College of Engineering. “In this paper, we show a blueprint of such a microfluidic device with micromixers connected in parallel to trap and grow crystals under multiple conditions simultaneously.”
In their study, the researchers found that the device was able to screen for polymorphs, morphology and growth rates of L-histidine under eight different conditions. Conditions included variations in molar concentration, percent ethanol by volume, and supersaturation – important variables that influence the rate of crystal growth. The overall screening time for L-histidine using the multi-well microfluidic device was approximately 30 minutes, which is at least eight times shorter than a sequential screening process.
The researchers also compared the results of the screening with a conventional device. They found that the conventional device significantly overestimated the stable form fraction and showed high uncertainty in the measured growth rates.
“The multiwell microfluidic device paves the way for next generation microfluidic devices that lend themselves to automation for high throughput screening of crystalline materials,” Singh said. Better screening devices can improve the development efficiency of API processes and enable fast and robust drug manufacturing, he said, which could ultimately lead to safer and cheaper drugs.
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