Impact of Inequivalent Wetting on the Face-Specific Dissolution Rates for Single Faceted-Crystals Predicted from Solid-State Binding Energies.

A methodology for the prediction of face-specific relative dissolution rates for single-faceted crystals accounting for inequivalent wetting by the solvent is presented. This method is an extended form of a recent binding energy model developed by the authors (Najib et al., Cryst. Growth & Des. 2021, 21(3), 1482-1495) for predicting the face-specific dissolution rates for single-faceted crystals from the solid-state intermolecular binding energies in a vacuum. The principal modification is that the equivalent wetting of the crystal surfaces is no longer assumed, since interactions between the crystal surfaces and the solution-state molecules are incorporated. These surface interactions have been investigated by using a grid-based systematic search method. The face-specific dissolution rates predicted by the extended binding energy model for ibuprofen in a 95% v/v ethanol-water solution and furosemide in an aqueous medium have been validated against the published experimental results and are in excellent agreement. This model is a step forward toward accurate predictions of the relative face-specific dissolution rates for a wide variety of faceted crystals in any dissolution medium.

Characterization of Mass Transfer within the Crystal-Solution Boundary Layer of l-Alanine {120} Faces Using Laser Interferometry during Growth and Dissolution.

Crystallization and dissolution are important processes to consider in drug development as well as many other industrial processes. Many current growth and dissolution models are based on bulk solution properties and do not implicitly consider concentration variation close to the crystal surface-solution interface and how this is mediated by solute diffusive mass transfer. Solution boundary layer thickness and concentration distribution, for the {120} crystal habit face of single crystals of l-alanine in saturated aqueous solutions during both growth and dissolution processes, is measured as a function of super/undersaturation using a Mach-Zehnder optical interferometer system. Further analysis allows determination of the diffusion coefficient and mass flux within the boundary layer as well as whether the processes are controlled by mass transfer or crystal interfacial kinetics. The measurement of this study revealed that the {120} face was not saturated at its surface during growth or dissolution meaning both processes were somewhat limited by their crystal interfacial kinetics. Growth was limited by crystal interfacial kinetics at all supersaturations to the same degree, whereas dissolution had a mixed dependency on crystal interfacial kinetics and mass transfer at lower undersaturations becoming more limited by mass transfer at higher undersaturations. Boundary layer thickness increased with super/undersaturation but to a lesser degree than the increase in the concentration difference between the crystal surface and bulk solution leading to a higher mass flux of solute molecules through the boundary layer. At the same relative super/undersaturation mass flux of solute molecules was faster during dissolution which was concurrent with its increased surface to bulk solution concentration difference and boundary layer thickness.

An interlaboratory investigation of intrinsic dissolution rate determination using surface dissolution.

The purpose of this study was to conduct an interlaboratory ring-study, with six partners (academic and industrial), investigating the measurement of intrinsic dissolution rate (IDR) using surface dissolution imaging (SDI) equipment. Measurement of IDR is important in pharmaceutical research as it provides characterising information on drugs and their formulations. This work allowed us to assess the SDI's interlaboratory performance for measuring IDR using a defined standard operating procedure (see supporting information) and six drugs assigned as low (tadalafil, bromocriptine mesylate), medium (carvedilol, indomethacin) and high (ibuprofen, valsartan) solubility compounds. Fasted State Simulated Intestinal Fluid (FaSSIF) and blank FaSSIF (without sodium taurocholate and lecithin) (pH 6.5) were used as media. Using the standardised protocol an IDR value was obtained for all compounds and the results show that the overall IDR rank order matched the solubility rank order. Interlaboratory variability was also examined and it was observed that the variability for lower solubility compounds was higher, coefficient of variation >50%, than for intermediate and high solubility compounds, with the exception of indomethacin in FaSSIF medium. Inter laboratory variability is a useful descriptor for understanding the robustness of the protocol and the system variability. On comparison to another published small-scale IDR study the rank ordering with respect to dissolution rate is identical except for the high solubility compounds. This results indicates that the SDI robustly measures IDR however, no recommendation on the use of one small scale method over the other is made.

The double solubility rule holds for racemizing enantiomers.

Chiral amnesia: Experimental results demonstrate that the double solubility rule indeed holds true for the solution-phase enantiomers of a conglomerate-forming solid under fast-racemizing conditions. There is neither experimental evidence for chiral recognition via solution-phase clusters nor a need to invoke them to produce a lucid explanation of the compelling model for the evolution of solid-phase homochirality first communicated by Viedma.

Evolution of solid phase homochirality for a proteinogenic amino acid.

The inexorable evolution of solid-phase single chirality is demonstrated for the first time for a proteinogenic amino acid. Enantioenrichment is observed both under attrition-enhanced conditions and without the aid of particle grinding. Differences in the form of the conversion profiles for the process under the two sets of conditions provide suggestions concerning the mechanism of the transformation.

Emergence of solution-phase homochirality via crystal engineering of amino acids.

The evolution of homochirality from a prebiotic environment has long intrigued scientists. Here we report how highly enantioenriched solutions may be produced by manipulation of amino acid phase behavior, a concept that has far-reaching implications for prebiotic chemistry. We demonstrate that the eutectic composition of aqueous mixtures of L and D amino acids may be tuned by the addition of achiral dicarboxylic acids that cocrystallize with chiral amino acids. We find that, in several cases, these systems yield new eutectic compositions of 98% ee or higher. This work suggests a forerunner of modern crystal engineering that provides a general and facile mechanism for the evolution of homochirality as well as a conceptual advance for the separation of enantiomers of molecules forming racemic compounds.