Solvent compatible microfluidic platforms for solid form screening of pharmaceutical parent compounds

Microfluidics;solid form screening;solvent compatible;liquid-liquid extraction;pharmaceutical parent compound;raman spectroscopy;X-ray diffraction

Goyal, Sachit

关键词: Microfluidics;    solid form screening;    solvent compatible;    liquid-liquid extraction;    pharmaceutical parent compound;    raman spectroscopy;    X-ray diffraction;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/49791/Sachit_Goyal.pdf?sequence=1&isAllowed=y

美国|英语

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

【 摘 要 】

A significant fraction of candidate pharmaceutical parent compounds (PCs) are rejected on account of poor physicochemical properties that affect their biopharmaceutical attributes such as bioavailability, toxicity, and stability.Hence, a major factor contributing to the high costs and turnaround times associated with drug development involves the laborious characterization of physicochemical properties of thousands of compounds in the drug development process. The physicochemical properties of these compounds are typically determined by screening, crystallization, and subsequent analysis of various solid forms of a compound obtained. Currently the solid form screening process is performed by robotic platforms that require on the order of 0.5 g of material to screen 100 conditions.As a result, this screening effort is postponed to later stages in the drug development process, until sufficient material is available and hence majority of the PCs are forcefully brought forward in the drug development cycle, only to realize later that their solid forms may not be suitable for formulation.Solid form screening with reduced sample requirement per condition will allow the identification of enabling solid forms of PCs and their crystallization conditions at an early stage. Exploring enabling solid forms and applying them in the early stage would significantly reduce the cost of drug development associated with the switch of solid forms.Microfluidics has the potential to screen for solid forms of PCs using significantly smaller quantities of materials (~5 μg per condition), thereby enabling high throughput screening for suitable solid forms in the crucial early stages of development when only limited amounts of PC (typically 10 mg) are available.In addition, microfluidics offers more precise control over fluid flow and transport, composition, and kinetics of a crystallization trial compared to conventional methods. The microfluidic crystallization platforms reported in this work enable high throughput (24-288 sub-microliter well arrays), combinatorial solid form screening of PCs (e.g., salts, cocrystals, and polymorphs) employing a wide range of modes of crystallization including diffusive mixing, antisolvent addition, seeding, and solvent evaporation while utilizing significantly smaller quantities of materials (~5 μg per condition). The developed platforms are compatible with a wide range of solvents commonly used in pharmaceutical crystallization (polar as well as non-polar organic solvents), exhibit minimal solvent loss (enabling long-term crystallization experiments), allow on-chip solid form characterization via Raman spectroscopy and / or X-ray analysis, circumventing the need to manually harvest crystals and potentially damage them, as well as enable portability between sample loading and analysis stations. Development of multilayer PDMS-based and hybrid polymer-based microfluidic platforms and their application to solid form screening via diffusive mixing and antisolvent addition crystallization modes is discussed in chapters 2-4.An on-chip seeding-based crystallization optimization method to enhance crystal quality, and X-ray data collection and analysis method to solve structures of pharmaceutical solid forms is discussed in chapter 5. The development and application of a hybrid multilayer polymer-based microfluidic platform that enables controlled and variable solvent evaporation-based solid form screening of pharmaceuticals is discussed in chapter 6.The employment of appropriate polymers for chip fabrication enabled solvent compatibility with polar organic solvents typically used in pharmaceutical industry (e.g., alcohols, acetonitrile, water, and DMSO) and on-chip analysis of the crystallized solid forms via Raman and X-ray. The development and application of hybrid perfluoropolyether-based microfluidic platforms for solid form screening of PCs with enhanced solvent resistance (polar as well as non-polar organic solvents) while retaining the high throughput screening and on-chip analysis capabilities is discussed in chapter 7.The microfluidic platforms developed in this work 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. The microfluidic platforms developed in this work can further be employed for a multitude of applications including studying the effect of additives (e.g., polymers, antisolvents, surfactants) on crystal habit and polymorphism, studying the solution-based transformation of solid forms, as well as studying crystallization nucleation and growth kinetics of pharmaceuticals. In this work, the development and application of hybrid polymer-based microfluidic platforms for liquid-liquid extraction applications in the pharmaceutical industry including purification of radioactive metals for radiopharmaceutical synthesis and drug lipophilicity studies is also discussed in chapter 8.