Face-Discriminating Dissolution Kinetics of Furosemide Single Crystals: In Situ Three-Dimensional Multi-Microscopy and Modeling

Abstract

A versatile in situ multi-microscopy approach to study the dissolution kinetics of single crystals is described, using the loop diuretic drug furosemide as a testbed to demonstrate the utility of the approach. Using optical microscopy and scanning ion-conductance microscopy (SICM) in combination, the dissolution rate of individual crystallographically independent crystal faces can be measured quantitatively while providing a direct visualization of the evolution of crystal morphology in real time in three dimensions. Finite element method (FEM) models using experimental data enables quantitative analysis of dissolution fluxes for individual faces and determination of the limiting process -mass transport or interfacial kinetics -that regulates dissolution. A key feature of the approach is that isolated crystals (typically < 60 µm largest characteristic dimension) in solution during dissolution experience high and well defined diffusion rates. The ability to obtain this quantitative information for individual crystal faces suggests a pathway to understanding crystal dissolution at the molecular level and regulating bioavailability, for example, through manipulation of crystal morphology. AbstractA versatile in situ multi-microscopy approach to study the dissolution kinetics of single crystals is described, using the loop diuretic drug furosemide as a testbed to demonstrate the utility of the approach. Using optical microscopy and scanning ion-conductance microscopy (SICM) in combination, the dissolution rate of individual crystallographically independent crystal faces can be measured quantitatively while providing a direct visualization of the evolution of crystal morphology in real time in three dimensions. Finite element method (FEM) models using experimental data enable quantitative analysis of dissolution fluxes for individual faces and determination of the limiting process -mass transport or interfacial kinetics -that regulates dissolution. A key feature of the approach is that isolated crystals (typically < 60 µm largest characteristic dimension) in solution during dissolution experience high and well defined diffusion rates. The ability to obtain this quantitative information for individual crystal faces suggests a pathway to understanding crystal dissolution at the molecular level and regulating bioavailability, for example, through manipulation of crystal morphology.

Implication of Differential Surface Anisotropy on Biopharmaceutical Performance of Polymorphic Forms of Ambrisentan

“…Formation of defects and undulated surface leads to an increase in specific surface area and microdomains of higher surface energy that plays an important role in increasing the dissolution rate. 28 To understand this phenomenon, the IDR compacts were studied by AFM images. The formation of a defect in form II gives enough evidence of interaction of surface hydrophilic moieties with dissolution medium.…”

Electrochemistry and Optical Microscopy

“…It is illusory to seek for absolute optical measurement. One would rather evaluate relative variations of a quantity (mass, volume, etc…) from optical intensity variations and resort to calibration procedures to verify the predicted trends, using different molecular probes or NP gauges, and cross-correlating the optical images with multiple microscopic observations [75][76][77][78]. Resolution is the ability of an imaging tool to distinguish (resolve) in an image two objects.…”

Multifunctional scanning ion conductance microscopy

“…Alternatively, time-dependent simulations can be performed, based on the initial state of the system, which help to provide physical insights into dynamic (transport) processes and timescales [44,92]. We consider here the use of FEM models for the types of SICM studies carried out hitherto, but note that extension to other processes such as mixing [93], crystal growth and dissolution [94], heat transfer problems [95] and the study of electrodes and electrical components [96] is straightforward. We outline below ( §5) how FEM simulations can be used to understand and predict the current-potential response of a charged nanopipette in the vicinity of a charged interface in an SICM experiment [41,42,44], from which, in turn, surface charge values can be quantified.…”