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.

Polymorphism in molecular crystals is a prevalent phenomenon and is of great interest to the pharmaceutical community. The solid-state form is a key quality attribute of a crystalline product. Inconsistencies in the solid phase produced during the manufacturing and storage of drug substances and drug products may have severe consequences. It is essential to understand the solid-state behavior of the drug and to judiciously select the optimal solid form for development. This review highlights the pervasiveness and relevance of polymorphism and describes solid form screening and selection processes. Moreover, case studies on controlling polymorphs from a chemical development perspective are provided.

Patterned glycine crystals nucleated on functionalized metallic square islands. This approach can be used to fabricate particles with micron dimensions and screen solid forms under different conditions. The size of the glycine crystals is controlled by the dimensions of the islands. High energy metastable beta-glycine crystallizes on small metallic islands, whereas for large islands, the polymorphic outcome becomes biased toward the alpha-form.

The solution-mediated phase transformation of the metastable A form of an active pharmaceutical ingredient (1) to the stable B form is investigated in 2-propanol. The transformation behavior (or rate) is quantified using powder X-ray diffraction. The studies show that the rate of transformation is sensitive to the tailor-made impurities and that the presence of certain inhibitors reduces the rate of transformation. Concurrently molecular modeling studies are undertaken to investigate the incorporation of these structurally related impurities into the crystal lattice, and it is observed that the build-in approach used in morphology predictions for additive-host systems can be applied to evaluate the extent of impurity incorporation. The build-in approach employs the attachment energy method in which the host molecules are substituted by impurity molecules, and the relative incorporation energies are calculated for various crystal faces. The order of the relative incorporation energies of the structurally similar impurities is identical to the order of the percentages of the amount of impurities incorporated into the crystal lattice as determined by high performance liquid chromatography (HPLC).

This study demonstrates the effect of the solution pH on the polymorphic outcome of glycine by evaporation-driven crystallization from aqueous solution. More than 2000 solution droplets under identical conditions were generated using a patterned self-assembled monolayers (SAMs) substrate. Each droplet on the substrate serves as an independent crystallization trial. Glycine nucleated inside the droplets through solvent evaporation, and their polymorphic forms were identified via Raman microscopy. Three different polymorphic forms of glycine (R-, β-, and γ-forms) simultaneously crystallized at all conditions employed. The probability of producing the thermodynamically stable γ-glycine from acidic (pH 3.40) or basic solution (pH 10.10) droplets significantly increased when compared with neutral aqueous solution (pH ∼ 6.00) droplets.

Multiple 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.

The primary goal of crystallization process is to generate particles with controlled size, shape and solid form, and the desired chemical purity. Many different types of approaches including molecular level strategies have been devised and employed to control the final structure of crystals. One promising approach is the utilization of self-assembled monolayers (SAMs) as templates. Recently, we reported that single glycine crystals can nucleate on patterned metallic square islands, with the size and morphology of the particles controlled by the dimensions of the islands or the concentration of the solution. Herein, the effect of the solution concentration on the polymorphic outcome of glycine crystals confined to hydrophilic metallic islands is investigated. Furthermore, we examine how variations in the solvent evaporation rate can impact the polymorph distribution of glycine.

Small droplets of supersaturated hen egg white lysozyme (HEWL) solution were exposed to intense linearly polarized laser pulses with different wavelengths, intensities, and pulse durations. Laser irradiation under some conditions significantly increased the number of droplets in which crystals were observed in a given time period, compared with nonirradiated samples. As a general rule, nonphotochemical laser induced nucleation (NPLIN) in lysozyme solutions was more effective with shorter aging time, 532-nm wavelength, higher peak intensity, and shorter pulse duration. Bovine pancreatic trypsin (BPT) was also examined using NPLIN, showing the potential application of NPLIN to other proteins.