Accelerated Forced Degradation of Pharmaceuticals in Levitated Microdroplet Reactors

Abstract

Forced degradation is a method of studying the stability of pharmaceuticals in order to design stable formulations and predict drug product shelf life. Traditional methods of reaction and analysis usually take multiple days, and include LC-UV and LC-MS product analysis. In this study, the reaction/analysis sequence was accelerated to be completed within minutes using Leidenfrost droplets as reactors (acceleration factor: 23-188) and nanoelectrospray ionization MS analysis. The Leidenfrost droplets underwent the same reactions as seen in traditional bulk solution experiments for three chemical degradations studied. This combined method of accelerated reaction and analysis has the potential to be extended to forced degradation of other pharmaceuticals and to drug formulations. Control of reaction rate and yield is achieved by manipulating droplet size, levitation time and whether or not make-up solvent is added. Evidence is provided that interfacial effects contribute to rate acceleration.

A microdroplet-accelerated Biginelli reaction: mechanisms and separation of isomers using IMS-MS

“…55 This acceleration presumably arises as the microdroplet evaporates, a process that leads to high concentrations of reagents in conned spaces. Additional factors such as change in pH, 27,28 droplet size, 28,29 reagent concentration, 28,34,46 solvent system, 17,30 and droplet temperature, 30,31 may also inuence these reactions.…”

“…Recently, the groups of Cooks, [17][18][19][20][21][22][23][24][25][26] Zare, [27][28][29][30][31][32][33][34][35][36][37][38][39] and others [40][41][42][43][44][45][46] have reported the acceleration of reactions in microdroplet environments during the process of electrospraying reagents into a mass spectrometer. 32 Intrigued by the possibility of faster rates for multicomponent reactions, we explored the use of microdroplets as a means of enabling a rapid Biginelli reaction (Scheme 2).…”

High yield accelerated reactions in nonvolatile microthin films: chemical derivatization for analysis of single-cell intracellular fluid

“… 17 , 18 Compared to homogeneous bulk phase reactions, these emerging studies using highly reactive interfaces lead to high reaction rates and favorable product yields. In addition to these cases, reactions are also known to be accelerated by one to five orders of magnitude 19 relative to those in bulk when they take place in small confined volumes such as in electrosprayed microdroplets, 20 – 25 levitated neutral droplets 26 – 28 or thin films. 20 , 28 – 30 In each of these systems, the reaction mixture undergoes solvent evaporation to generate large surface to volume ratio compartments where reactants are concentrated and rate constants may be increased by interfacial effects.…”

“…As accelerated reaction rates and satisfactory yields follow upon solvent evaporation, the issue is how to effectively control solvent evaporation to make the system stable in the solvent-poor state so as to drive the reaction at a high rate and achieve satisfactory yields. In the past few years, efforts have been made by our groups and others 26 – 30 , 32 , 33 to achieve this goal. For example, in Leidenfrost droplet synthesis, the solvent can be added back continuously to the levitated droplet to compensate for the solvent loss by evaporation, thus increasing the reaction time in a small controlled-volume reactor.…”

Chemoselective N‐Alkylation of Indoles in Aqueous Microdroplets

“…Microdroplet synthesis has been scaled up to a production rate of about 1–30 mg min −1 , which makes it preparative . This tempting feature of microdroplet reactions also stimulates its application in many fields, such as high‐throughput reaction screening, preparation of gold nanostructures, and accelerated degradation of pharmaceuticals …”