Crystal Nucleation Using Surface-Energy-Modified Glass Substrates

Abstract

Systematic surface energy modifications to glass substrates can induce nucleation and improve crystallization outcomes for small molecule active pharmaceutical ingredients (APIs) and proteins. A comparatively broad probe for function is presented in which various APIs, proteins, organic solvents, aqueous media, surface energy motifs, crystallization methods, form factors, and flat and convex surface energy modifications were examined. Replicate studies (n ≥ 6) have demonstrated an average reduction in crystallization onset times of 52(4)% (alternatively 52 ± 4%) for acetylsalicylic acid from 91% isopropyl alcohol using two very different techniques: bulk cooling to 0 °C using flat surface energy modifications or microdomain cooling to 4 °C from the interior of a glass capillary having convex surface energy modifications that were immersed in the solution. For thaumatin and bovine pancreatic trypsin, a 32(2)% reduction in crystallization onset times was demonstrated in vapor diffusion experiments (n ≥ 15). Nucleation site arrays have been engineered onto form factors frequently used in crystallization screening, including microscope slides, vials, and 96- and 384-well high-throughput screening plates. Nucleation using surface energy modifications on the vessels that contain the solutes to be crystallized adds a layer of useful variables to crystallization studies without requiring significant changes to workflows or instrumentation.

The heterogeneous crystallization of a novel solvate of clozapine base in the presence of excipients

“…10 Crystallisation from solution occurs with the solute molecules undergoing molecular recognition, aggregation (concentration fluctuation) and pre-organisation processes in a supersaturated solution, leading to the formation of heterophases (nuclei) which act as centres of crystallisation. 11 Foreign substrates in contact with the supersaturated solution can perform a significant role in heterogeneous primary nucleation by lowering the free energy and/or increasing the pre-exponential factor required for nucleation. 12 In the literature, a variety of surfaces such as polymers, [13][14][15][16] selfassembled monolayers, 17 excipients, 18,19 metallic surfaces, 13,20 and surface coatings using organosilanes 21,22 have been widely studied as heterosurfaces to control nucleation.…”

Oriented Crystallization on Organic Monolayers to Control Concomitant Polymorphism

“…can assist in narrowing down experimental conditions to isolatea preferred form. [10][11][12] Neat ands olvent-assisted mechanochemical grinding, solution evaporation techniques, and supersaturation levels are usefulb ut they are not regarded as efficient for polymorph screening purposes. Therefore, high-throughput screening, which can be used to explore different phase spaces is necessary to growaparticular form in ap ure and reproducible manner.…”

“…[16] To overcome such issues in addition to conventionalm ethods of choosingd ifferents olvents, supersaturation levels, temperatures, cooling rates,a nd pH values, av ariety of complementary approaches have also been pursued in recent years. [7] Crystal-lization in confined spaces, [12] such as capillaries and micropores,o ri nt he presence of molecular or polymerica dditives, [17] use of SAM (Figure 1a), [18] gel-phase crystallization, [19] laser technology, [20] high temperature, [15] etc. have been used with some success.…”

“…Essentially the use of a range of solvents for crystallization, control of temperature, cooling/evaporation rates, pH, additives etc. can assist in narrowing down experimental conditions to isolate a preferred form . Neat and solvent‐assisted mechanochemical grinding, solution evaporation techniques, and supersaturation levels are useful but they are not regarded as efficient for polymorph screening purposes.…”

Facile Chemical Solution Transportation for Direct Recycling of Iron Oxide Rust Waste to Hematite Films

“…For instance, strong interaction of biphenyl dicarboxylic acid with the step edges on Cu caused an edge passivation and impeded the mass diffusion and film growth . Through tuning the surface energies of glass substrate, the nucleation and crystallization of small pharmaceutical molecules or protein could be improved . In addition, the biomineralization of CaCO 3 films required a polymer substrate for enhanced ion absorption and nucleation .…”