Erica Gunn

Stability of Amorphous Pharmaceutical Solids: Crystal Growth Mechanisms and Effect of Polymer Additives

We review recent progress toward understanding and enhancing the stability of amorphous pharmaceutical solids against crystallization. As organic liquids are cooled to become glasses, fast modes of crystal growth can emerge. One such growth mode, the glass-to-crystal or GC mode, occurs in the bulk, and another exists at the free surface, both leading to crystal growth much faster than predicted by theories that assume diffusion defines the kinetic barrier of crystallization. These phenomena have received different explanations, and we propose that GC growth is a solid-state transformation enabled by local mobility in glasses and that fast surface crystal growth is facilitated by surface molecular mobility. In the second part, we review recent findings concerning the effect of polymer additives on crystallization in organic glasses. Low-concentration polymer additives can strongly inhibit crystal growth in the bulk of organic glasses, while having weaker effect on surface crystal growth. Ultra-thin polymer coatings can inhibit surface crystallization. Recent work has shown the importance of molecular weight for crystallization inhibitors of organic glasses, besides “direct intermolecular interactions” such as hydrogen bonding. Relative to polyvinylpyrrolidone, the VP dimer is far less effective in inhibiting crystal growth in amorphous nifedipine. Further work is suggested for better understanding of crystallization of amorphous organic solids and the prediction of their stability.

Twisted Mannitol Crystals Establish Homologous Growth Mechanisms for High-Polymer and Small-Molecule Ring-Banded Spherulites

D-Mannitol belongs to a large and growing family of crystals with helical morphologies (Yu, L. J. Am. Chem. Soc.2003, 125, 6380). Two polymorphs of D-mannitol, α and δ, when grown in the presence of additives such as poly(vinylpyrrolidone) (PVP) or D-sorbitol, form ring-banded spherulites composed of handed helical fibrils, where the helix axes correspond to the radial growth directions. The two polymorphs form helices with opposite senses in the presence of PVP but the same sense in the presence of D-sorbitol. The characteristic dimensions of the fibrils, including thickness, aspect ratio, and pitch, were determined by scanning probe and electron microscopies. These values must form the basis of any theory that presupposes what forces give rise to crystal twisting, a problem that has been broached but unsettled in the literature of polymer crystallization. The interdependence of the rhythmic variations of both linear and circular birefringence, as determined by Mueller matrix microscopy, informs the cooperative organization of mannitol fibers. The microstructure of mannitol ring-banded spherulites compares favorably to that of high polymers and is evaluated within the context of current theories of crystal twisting.

Low-concentration polymers inhibit and accelerate crystal growth in organic glasses in correlation with segmental mobility.

Crystal growth in organic glasses has been studied in the presence of low-concentration polymers. Doping the organic glass nifedipine (NIF) with 1 wt % polymer has no measurable effect on the glass transition temperature Tg of host molecules, but substantially alters the rate of crystal growth, from a 10-fold reduction to a 30% increase at 12 °C below the host Tg. Among the polymers tested, all but polyethylene oxide (PEO) inhibit growth. The inhibitory effects greatly diminish in the liquid state (at Tg + 38 °C), but PEO persists to speed crystal growth. The crystal growth rate varies exponentially with polymer concentration, in analogy with the polymer effect on solvent mobility, though the effect on crystal growth can be much stronger. The ability to inhibit crystal growth is not well ordered by the strength of host-polymer hydrogen bonds, but correlates remarkably well with the neat polymers Tg, suggesting that the mobility of polymer chains is an important factor in inhibiting crystal growth in organic glasses. The polymer dopants also affect crystal growth at the free surface of NIF glasses, but the effect is attenuated according to the power law us ∝ ub(0.35), where us and ub are the surface and bulk growth rates.

Simultaneous false-colour imaging of birefringence, extinction and transmittance at camera speed.

A polarized light imaging technique is introduced that simultaneously captures and unfolds transmittance, fast/slow axes directions and birefringence or linear dichroism from single camera exposures. The technique, based on the rotating polarizer method, is capable of sampling an object through polarizers at four different angles in a single image with the use of an image multiplexer. The range of possible applications is demonstrated with examples from the fields of biology, medicine, forensics and material sciences.

Fast Surface Crystal Growth on Molecular Glasses and Its Termination by the Onset of Fluidity

Organic glasses can grow crystals much faster on the free surface than in the interior, a phenomenon important for fabricating stable amorphous materials. This surface process differs from and is faster than the glass-to-crystal (GC) growth mode existing in the bulk of molecular glasses. We report that similar to GC growth, surface crystal growth terminates if glasses are heated to gain fluidity. In their steady growth below the glass transition temperature Tg, surface crystals rise above the amorphous surface while spreading laterally and are surrounded by depressed grooves. Above Tg, the growth becomes slower, sometimes unstable. This damage is stronger on segregated needles (α indomethacin, nifedipine, and o-terphenyl) than on crystals growing in compact domains (γ indomethacin). This effect arises because the onset of liquid flow causes the wetting and embedding of upward-growing surface crystals. Segregated needles are at greater risk because their slow-growing flanks appear stationary relative to liquid flow at a low temperature. The disruption of surface crystal growth by fluidity supports the view that the process occurs by surface diffusion, not viscous flow. Compared to the bulk GC mode, surface crystal growth is disrupted less abruptly by fluidity. Nevertheless, to the extent that fluidity damages them, both processes are solid-state phenomena terminated in the liquid state.

Extinction mapping of polycrystalline patterns

Descriptions of polycrystalline patterns require the quantitative characterization of the organization of many crystallites. Automated linear birefringence imaging systems developed during the past 15 years are well suited to mapping crystallite orientation. Here, the rotating polarizer method is applied to the optical textures of polycrystalline phthalic acid spherulites.

Polymorphism of 5-(pyridin-2-ylmethylene)-3-phenyl-2-methylthio-3,5-dihydro-4H-imidazole-4-one

The title compound, C16H13N3OS (1), exists in three polymorphic forms. Crystalline 1 undergoes an enantiotropic, first-order, k2 phase transition at 262.9(5) K with ΔH = 0.3(1) kJ mol−1. Upon cooling below the transition temperature, the high temperature orthorhombic polymorph (Form I, space groupPbcm) transforms into a low temperature orthorhombic polymorph (Form II, space groupPbca) with a unit cell twice the size of that of the Form I. A molten 1 can be cooled in a controlled fashion to generate a monoclinic Form III of 1 with the unit cell size similar to that of Form I. Metastable Form III, once isolated, is indefinitely stable between 100 K and its melting point of 466 K. If crystals of Form III are in contact with seed crystals of Form I, a monotropic t2 first-order Form III → Form I phase transition occurs upon heating with the onset between 420 and 448 K and ΔH = −1.7(4) kJ mol−1. The most substantial differences among the molecular geometries of 1 in Forms I–III are observed in the position and tilt of the phenyl ring relative to the rest of the molecule. The packing in Form III is very different from those in the other polymorphs. DFT molecular geometry optimizations produce the following order of stable molecule configurations: Form II (most stable), Form I (0.50 kJ mol−1), Form III (2.81 kJ mol−1).

Green challenges: student perspectives from the 2004 ACS-PRF Summer School on Green Chemistry

Participants in the American Chemical Society-Petroleum Research Fund (ACS-PRF) Summer School on Green Chemistry discuss the topics covered and lessons learned during the week-long summer school held July 31 through August 7, 2004, at Carnegie Mellon University. An outline of the program is accompanied by a discussion of the challenges and needs of the field of green chemistry as seen by the participants. These include further education of the public as well as members of the scientific community, thorough research and rigorous publication standards, and the formation of a cooperative and collaborative group of researchers.

Chiroptical imaging of crystals by mueller matrix microscopy

Mueller matrix microscopy is used to evaluate the heterogeneities and anisotropies in the circular birefringence and circular dichroism of crystalline materials.