Microfluidic platforms for solid form screening of pharmaceutical parent compounds

Pharmaceutical crystallization;solid form screening;combinatorial screening;microfluidics;Raman spectroscopy

Goyal, Sachit ; Kenis ; Paul J.A.

关键词: Pharmaceutical crystallization;    solid form screening;    combinatorial screening;    microfluidics;    Raman spectroscopy;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/26368/Goyal_Sachit.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Solid form screening and selection of pharmaceutical parent compounds (PCs) has been identified as a critical step in the early stages of drug development.A significant fraction of candidate PCs are rejected on account of poor physicochemical properties that affect their biopharmaceutical attributes such as bioavailability, toxicity, and stability.As a result, there is a pressing need to characterize these physicochemical properties early in the drug development process by exploring (1) all possible solid forms of a PC, and (2) the conditions favorable for formulation of these solid forms.While automated robotic systems have been developed to execute high throughput screens, these robotic tools typically require larger quantities of PC for solid form screening (~ 5 mg of material per condition) than are typically available in the initial phases of the drug development pipeline.Microfluidics has the potential to screen PCs using significantly smaller quantities of materials (~5 μg per condition), thereby enabling high throughput screening for suitable solid forms at the crucial early stages of development when only limited amounts of PC (typically 10 mg) are available.Here, we present PDMS-based microfluidic platforms that allow combinatorial mixing of PC and counter ion solutions in arrays of 24-48 sub-microliter wells enabling solid form screening by different modes of crystallization, viz. diffusive mixing, antisolvent addition, and solvent evaporation.These platforms are compatible with a wide range of solvents typically used for pharmaceutical crystallization, suffer from minimal solvent loss (enabling long-term experiments), allow improved control over solvent evaporation, and enable portability between sample loading and analysis stations.Additionally, these platforms enable on-chip characterization of the solid forms by Raman spectroscopy, circumventing the need to manually harvest crystals.The platforms were validated with several model compounds namely, naproxen, ephedrine, indomethacin, caffeine, theophylline, and tamoxifen.The microfluidic platforms developed here find immediate application in the pharmaceutical industry, as they require cheap and readily available external peripherals, such as pipettes and a vacuum source for operation.