Allan S. Myerson

Nucleation of Crystals from Solution: Classical and Two-Step Models

Crystallization is vital to many processes occurring in nature and in the chemical, pharmaceutical, and food industries. Notably, crystallization is an attractive isolation step for manufacturing because this single process combines both particle formation and purification. Almost all of the products based on fine chemicals, such as dyes, explosives, and photographic materials, require crystallization in their manufacture, and more than 90% of all pharmaceutical products contain bioactive drug substances and excipients in the crystalline solid state. Hence control over the crystallization process allows manufacturers to obtain products with desired and reproducible properties. We judge the quality of a crystalline product based on four main properties: size, purity, morphology, and crystal structure. The pharmaceutical industry in particular requires production of the desired crystal form (polymorph) to assure the bioavailability and stability of the drug substance. In solution crystallization, nucleation plays a decisive role in determining the crystal structure and size distribution. Therefore, understanding the fundamentals of nucleation is crucial to achieve control over these properties. Because of its analytical simplicity, researchers have widely applied classical nucleation theory to solution crystallization. However, a number of differences between theoretical predictions and experimental results suggest that nucleation of solids from solution does not proceed via the classical pathway but follows more complex routes. In this Account, we discuss the shortcomings of classical nucleation theory and review studies contributing to the development of the modern two-step model. In the two-step model that was initially proposed for protein crystallization, a sufficient-sized cluster of solute molecules forms first, followed by reorganization of that cluster into an ordered structure. In recent experimental and theoretical studies, we and other researchers have demonstrated the applicability of the two-step mechanism to both macromolecules and small organic molecules, suggesting that this mechanism may underlie most crystallization processes from solutions. Because we have observed an increase in the organization time of appropriate lattice structures with greater molecular complexity, we propose that organization is the rate-determining step. Further development of a clearer picture of nucleation may help determine the optimum conditions necessary for the effective organization within the clusters. In addition, greater understanding of these processes may lead to the design of auxiliaries that can increase the rate of nucleation and avoid the formation of undesired solid forms, allowing researchers to obtain the final product in a timely and reproducible manner.

Formation of nanosized organic molecular crystals on engineered surfaces.

The pharmaceutical industry has great interest in organic molecular nanosized crystals because their enhanced solubility and dissolution rate can potentially enhance drug bioavailability. In this work, patterned engineered surfaces were used to crystallize glycine with a lateral dimension below 200 nm in a confined volume while controlling supersaturation. Bifunctional patterned surfaces with hydrophilic islands, as small as 500 nm, surrounded by hydrophobic regions were prepared using lithography and self assembled monolayers. Individual glycine crystals under 200 nm were formed from the confined solutions wetting each hydrophilic island, while supersaturation was controlled by slow antisolvent diffusion. Individual crystals were characterized with AFM and Raman spectroscopy and determined to be the metastable beta form. The solubility enhancement as a function of crystal size was measured, and the solubility of crystals with a radius of 100 nm or less was estimated.

Concomitant polymorphism in confined environment.

PurposeThe aim of this paper is to demonstrate that multiple crystal forms can be generated on patterned self-assembled monolayers (SAMs) substrates in single experiments in a given solvent system.MethodsFunctionalized metallic islands are fabricated and utilized as individual templates for crystal formation. Taking advantage of the different wetting properties that patterned surfaces offered, arrays of small solution droplets on the nano- and pico- liter scale were produced on the substrates. Different droplet dimensions were deposited on the substrate. As the solvent evaporates from the droplets, crystals were formed within the constrained volume. Crystal habits were examined with optical microscopy while the solid form was identified with Raman microscopy.ResultsWith mefenamic acid (MA) and sulfathiazole as model pharmaceutical compounds, two and four different polymorphs, respectively, were observed under identical conditions. Moreover, it is established that the polymorphic distribution is highly dependent on the solvent evaporation rate and the solution concentration. These results imply that multiple crystal forms competitively nucleate in solution, and the probability of each form nucleating is strongly dependent on the supersaturation of the solution. Additionally, solvent was observed to play a role in controlling the solid state outcome.ConclusionsMultiple crystal forms can concomitantly nucleate on patterned substrates. This technique can particularly be attractive to screen for polymorphs as elusive, metastable solid forms are favored with the creation of high supersaturation and can be stabilized due to the minimal volumes generated.

Chiral Self Assembled Monolayers as Resolving Auxiliaries in the Crystallization of Valine

Chiral drugs are a subgroup of drug substances that contain one or more chiral centers. For reasons of safety and efficacy, the pure enantiomer is usually preferred over the racemate in many marketed dosage forms. Thus, resolution of racemic mixtures is an active area of research. In this work, chiral self assembled monolayers (SAMs) on gold were employed as resolving auxiliaries in the crystallization of the amino acid valine. Results showed the ability to obtain one enantiomer in excess on the crystals grown on the chiral SAMs when starting with racemic solutions. The enantiomer obtained in excess was the one having opposite chirality to the monolayer being used. In addition, it was possible to obtain crystals of the pure enantiomer when starting with a solution having an enantiomeric excess value of 50%. Control experiments carried out without chiral SAMs showed that at equilibrium, mixtures of the pure enantiomer and racemic compound were obtained under these conditions. The enantiomer obtained on the chiral SAMs was the one that was initially present in excess regardless of the chirality of the monolayer being used.